UniProtKB/Swiss-Prot Q8IV08: Variant p.Thr426Ala

5'-3' exonuclease PLD3
Gene: PLD3
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Variant information Variant position:

426 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LB/B The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Threonine (T) to Alanine (A) at position 426 (T426A, p.Thr426Ala). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties:

Change from medium size and polar (T) to small size and hydrophobic (A) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

0 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

Lowest score: -4 (low probability of substitution).
Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description:

No effect on protein maturation or trafficking to lysosomes; displays differential exonuclease activity depending on ssDNA sequence, showing increased activity toward ATP6 CpG-rich ssDNA sequence and normal activity toward ND4L CpG-rich ssDNA sequence; increases mitophagy rate. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs745463234 [ dbSNP | Ensembl ]

Sequence information Variant position:

426 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

490 The length of the canonical sequence.
Location on the sequence:

QARIPYARVNHNKYMVTERA T YIGTSNWSGNYFTETAGTSL The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         QARIPYARVNHNKYMVTERATYIGTSNWSGNYFTETAGTSL

Mouse                         QARIPYARVNHNKYMVTERASYIGTSNWSGSYFTETAGTSL

Rat                           QARIPYARVNHNKYMVTERTTYIGTSNWSGSYFTETAGTSL

Bovine                        QARIPYARVNHNKYMVTERATYIGTSNWSGSYFTETAGTSL

Xenopus laevis                QKKIPYARVNHNKYMVTDRVAYIGTSNWSGDYFINTAGSAL

Xenopus tropicalis            QKKIPYARVNHNKYMVTDRVAYIGTSNWSGDYFIHTAGSAL

Sequence annotation in neighborhood:

The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

Type: the type of sequence feature.
Positions: endpoints of the sequence feature.
Description: contains additional information about the feature.

Type	Positions	Description
Chain	1 – 490	5'-3' exonuclease PLD3
Topological domain	60 – 490	Lumenal
Domain	411 – 437	PLD phosphodiesterase 2
Active site	416 – 416	Nucleophile
Binding site	416 – 416
Binding site	438 – 438
Disulfide bond	366 – 487
Mutagenesis	410 – 410	P -> S. No effect on exonuclease activity toward ssDNA.
Mutagenesis	411 – 411	Y -> A. Decreases exonuclease activity toward RNA and ssDNA.
Mutagenesis	416 – 416	H -> A. Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes.
Mutagenesis	416 – 416	H -> N. Decreases RNA binding; when associated with N-201 and D-337. Almost complete loss of RNA binding; when associated with N-201 and D-340.
Mutagenesis	418 – 418	K -> A. Loss of (S,S)-BMP synthase activity. Loss of exonuclease activity toward ssDNA. No effect on protein expression or localization to lysosomes.
Mutagenesis	418 – 418	K -> R. Impairs myotube formation. Loss of exonuclease activity toward ssDNA. No effect on localization to lysosomes.
Mutagenesis	423 – 423	E -> A. Loss of (S,S)-BMP synthase activity. No effect on protein expression or localization to lysosomes. Loss of exonuclease activity toward ssDNA.
Mutagenesis	423 – 423	E -> D. No effect on (S,S)-BMP synthase activity, protein expression or localization to lysosomes.
Mutagenesis	432 – 432	N -> A. Loss of exonuclease activity toward ssDNA. No effect on protein localization to lysosomes.
Beta strand	426 – 431

Literature citations
Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease in a European consortium cohort.
Cacace R.; Van den Bossche T.; Engelborghs S.; Geerts N.; Laureys A.; Dillen L.; Graff C.; Thonberg H.; Chiang H.H.; Pastor P.; Ortega-Cubero S.; Pastor M.A.; Diehl-Schmid J.; Alexopoulos P.; Benussi L.; Ghidoni R.; Binetti G.; Nacmias B.; Sorbi S.; Sanchez-Valle R.; Llado A.; Gelpi E.; Almeida M.R.; Santana I.; Tsolaki M.; Koutroumani M.; Clarimon J.; Lleo A.; Fortea J.; de Mendonca A.; Martins M.; Borroni B.; Padovani A.; Matej R.; Rohan Z.; Vandenbulcke M.; Vandenberghe R.; De Deyn P.P.; Cras P.; van der Zee J.; Sleegers K.; Van Broeckhoven C.;
Hum. Mutat. 36:1226-1235(2015)
Cited for: LACK OF INVOLVEMENT IN ALZHEIMER DISEASE; VARIANTS SER-63; ALA-76; MET-159; CYS-162; SER-173; GLY-175; CYS-188; HIS-222; MET-232; GLN-242; GLY-249; CYS-272; SER-284; VAL-293; LEU-297; TYR-300; PRO-308; ILE-358; ALA-426 AND ARG-429; Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Van Acker Z.P.; Perdok A.; Hellemans R.; North K.; Vorsters I.; Cappel C.; Dehairs J.; Swinnen J.V.; Sannerud R.; Bretou M.; Damme M.; Annaert W.;
Nat. Commun. 14:2847-2847(2023)
Cited for: FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANTS MET-232; SER-284 AND ALA-426; MUTAGENESIS OF MET-6; LYS-228 AND ASN-236;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.