rs281865424
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000550.3(TYRP1):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,528 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000550.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TYRP1 | NM_000550.3 | c.1067G>A | p.Arg356Gln | missense_variant | Exon 5 of 8 | ENST00000388918.10 | NP_000541.1 | |
TYRP1 | XM_047423841.1 | c.862G>A | p.Glu288Lys | missense_variant | Exon 4 of 5 | XP_047279797.1 | ||
LURAP1L-AS1 | NR_125775.1 | n.317-1798C>T | intron_variant | Intron 3 of 3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151960Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250454Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135334
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1460568Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31AN XY: 726600
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74198
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the TYRP1 protein (p.Arg356Gln). This variant is present in population databases (rs281865424, gnomAD 0.01%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 16704458, 21739261, 28266639). This variant is also known as c.1066G>A. ClinVar contains an entry for this variant (Variation ID: 17596). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYRP1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Observed with a second TYRP1 variant in unrelated patients in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 16704458, 21739261, 34838614); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23862152, 28661582, 37956964, 35547362, 38542347, 30868578, 28266639, 34838614, 16704458, 21739261) -
Oculocutaneous albinism type 3 Pathogenic:1
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Nonsyndromic Oculocutaneous Albinism Pathogenic:1
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TYRP1-related disorder Pathogenic:1
The TYRP1 c.1067G>A variant is predicted to result in the amino acid substitution p.Arg356Gln. This variant has been reported in the homozygous and compound heterozygous state in individuals with oculocutaneous albinism (Rooryck et al. 2006. PubMed ID: 16704458; Shahzad et al. 2017. PubMed ID: 28266639; Zhang et al. 2011. PubMed ID: 21739261). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-12702424-G-A). Given the evidence, we interpret c.1067G>A (p.Arg356Gln) as pathogenic. -
Oculocutaneous albinism type 3;C2677086:MELANESIAN BLOND HAIR Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at