rs61754392
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000372.5(TYR):c.1255G>A(p.Gly419Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,611,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000372.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYR | NM_000372.5 | c.1255G>A | p.Gly419Arg | missense_variant | 4/5 | ENST00000263321.6 | |
TYR | XM_011542970.3 | c.1255G>A | p.Gly419Arg | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYR | ENST00000263321.6 | c.1255G>A | p.Gly419Arg | missense_variant | 4/5 | 1 | NM_000372.5 | P1 | |
TYR | ENST00000528243.1 | n.253G>A | non_coding_transcript_exon_variant | 2/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151782Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250446Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135352
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1460062Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43AN XY: 726362
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151782Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74122
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | TYR: PS4, PM2, PP1:Moderate, PP3, PP4, PS3:Supporting - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 419 of the TYR protein (p.Gly419Arg). This variant is present in population databases (rs61754392, gnomAD 0.04%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 16907708, 19865097, 27734839, 28266639, 32115698). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3792). 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 TYR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TYR function (PMID: 20861851). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2022 | Published functional studies demonstrate a lack of tyrosine hydroxylase and DOPA oxidase compared to wild type (Chaki et al., 2011); 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: 34426522, 1943686, 20861851, 28507374, 30996339, 28266639, 30868578, 33800529) - |
Tyrosinase-negative oculocutaneous albinism Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1991 | - - |
Pathogenic, no assertion criteria provided | research | Institute of Biotechnology and Microbiology, Bacha Khan University, Charsadda | - | - - |
Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 26, 2022 | - - |
Nonsyndromic Oculocutaneous Albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Mar 07, 2017 | - - |
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2023 | - - |
Oculocutaneous albinism type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 08, 2021 | We found this variant in a 1-year-old boy with OCA1 in the homozygous state. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at