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UniProtKB/Swiss-Prot P02786: Variant p.Tyr20His

Transferrin receptor protein 1
Gene: TFRC
Variant information

Variant position:  20
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
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 Tyrosine (Y) to Histidine (H) at position 20 (Y20H, p.Tyr20His).
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 large size and aromatic (Y) to medium size and polar (H)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  2
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:  In IMD46; increases protein expression; increases cell surface expression on T and B cells; increases soluble form level; impairs receptor internalization; impairs transferrin transport; impairs T and B cell proliferation as well as B cell class-switching; interacts with STEAP3; doesn't affect receptor internalization in erythroid precursor cells.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  20
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  760
The length of the canonical sequence.

Location on the sequence:   MMDQARSAFSNLFGGEPLS  Y TRFSLARQVDGDNSHVEMKL
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                         MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKL

                              MMDQARSAFSTLFGGEPLSYTRFSLARQVDGDNSHVEMKL

Mouse                         MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKL

Rat                           MMDQARSAFSNLFGGEPLSYTRFSLARQVDGDNSHVEMKL

Pig                           MMDQARSAFSSLFGGEPLSYTRFSLARQVDGDNSHVEMKL

Cat                           MMDQARSAFSTLFGGEPLSYTRFSLARQVDGDNSHVEMKL

Horse                         -MDQARSAFSNLFGGAPLSYTRFSLARQVDGDNSHVEMKL

Chicken                       -MDHARAALSNLFSVEPMSYTRFSIARQTDGDNSHVEMKL

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.

TypePositionsDescription
Chain 1 – 760 Transferrin receptor protein 1
Topological domain 1 – 67 Cytoplasmic
Region 1 – 67 Mediates interaction with SH3BP4
Motif 20 – 23 Endocytosis signal
Modified residue 10 – 10 Phosphoserine
Modified residue 19 – 19 Phosphoserine
Modified residue 20 – 20 Phosphotyrosine
Modified residue 21 – 21 Phosphothreonine
Modified residue 24 – 24 Phosphoserine
Mutagenesis 20 – 34 YTRFSLARQVDGDNS -> PPGYSLARQVDYTRF. No influence on endocytic uptake of the receptor.
Mutagenesis 20 – 23 YTRF -> PPGY. Only 16% as active as wild-type receptor.
Mutagenesis 20 – 20 Y -> C. Only 35% as active as wild-type receptor.
Mutagenesis 20 – 20 Y -> G. Only 20% as active as wild-type receptor.
Mutagenesis 21 – 21 T -> F. Only 88% as active as wild-type receptor.
Mutagenesis 21 – 21 T -> TA. Only 14% as active as wild-type receptor.
Mutagenesis 21 – 21 T -> TAA. Only 19% as active as wild-type receptor.
Mutagenesis 23 – 23 F -> Y. Only 48% as active as wild-type receptor.


Literature citations

A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.
Jabara H.H.; Boyden S.E.; Chou J.; Ramesh N.; Massaad M.J.; Benson H.; Bainter W.; Fraulino D.; Rahimov F.; Sieff C.; Liu Z.J.; Alshemmari S.H.; Al-Ramadi B.K.; Al-Dhekri H.; Arnaout R.; Abu-Shukair M.; Vatsayan A.; Silver E.; Ahuja S.; Davies E.G.; Sola-Visner M.; Ohsumi T.K.; Andrews N.C.; Notarangelo L.D.; Fleming M.D.; Al-Herz W.; Kunkel L.M.; Geha R.S.;
Nat. Genet. 48:74-78(2016)
Cited for: INVOLVEMENT IN IMD46; VARIANT IMD46 HIS-20; CHARACTERIZATION OF VARIANT IMD46 HIS-20; FUNCTION; INTERACTION WITH STEAP3;

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.