11-89227823-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000372.5(TYR):c.1037G>T(p.Gly346Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G346E) has been classified as Pathogenic.
Frequency
Consequence
NM_000372.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TYR | NM_000372.5 | c.1037G>T | p.Gly346Val | missense_variant, splice_region_variant | Exon 3 of 5 | ENST00000263321.6 | NP_000363.1 | |
TYR | XM_011542970.3 | c.1037G>T | p.Gly346Val | missense_variant, splice_region_variant | Exon 3 of 6 | XP_011541272.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250116Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135232
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460186Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726482
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74182
ClinVar
Submissions by phenotype
Oculocutaneous albinism type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Sep 05, 2023 | - - |
Abnormality of the eye Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | Rare ocular disorder associated to additional undetermined phenotypes - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 04, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 346 of the TYR protein (p.Gly346Val). This variant is present in population databases (rs773970123, gnomAD 0.007%). This missense change has been observed in individual(s) with ocular albinism (PMID: 16098056, 33800529). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437986). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 95%. This variant disrupts the p.Gly346 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8026428, 25216246, 28266639, 31077556). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at