rs863225436
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_001128148.3(TFRC):c.58T>C(p.Tyr20His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y20Y) has been classified as Likely benign.
Frequency
Consequence
NM_001128148.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TFRC | NM_001128148.3 | c.58T>C | p.Tyr20His | missense_variant | 3/19 | ENST00000360110.9 | |
TFRC | NM_003234.4 | c.58T>C | p.Tyr20His | missense_variant | 3/19 | ||
TFRC | NM_001313965.2 | c.-5-1214T>C | intron_variant | ||||
TFRC | NM_001313966.2 | c.-413+1725T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TFRC | ENST00000360110.9 | c.58T>C | p.Tyr20His | missense_variant | 3/19 | 1 | NM_001128148.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
TFRC-related combined immunodeficiency Pathogenic:2Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Combined immunodeficiency Pathogenic:1
Pathogenic, no assertion criteria provided | research | Geha Laboratory, Boston Childrens Hospital | Jan 15, 2015 | Patients with a combined immunodeficiency characterized by normal numbers, but impaired function, of T and B cells had a homozygous p.Tyr20His mutation in TFRC, encoding transferrin receptor 1 (TfR1). The mutation disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 surface expression. Iron citrate rescued the lymphocyte defects and transduction of wild type, but not mutant, TfR1 rescued impaired transferrin uptake in patient fibroblasts. TfrcY20H/Y20H mice recapitulated the patients’ immunologic defects. Despite the critical role of TfR1 in erythrocyte development and function, the patients had only mild anemia and only slightly TfR1 expression in their erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, can associate with TfR1 and partially rescues transferrin uptake in patient fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares the patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at