11-89178618-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP3BP4_Moderate
The NM_000372.5(TYR):āc.665T>Cā(p.Ile222Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,612,468 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I222I) has been classified as Likely benign.
Frequency
Consequence
NM_000372.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYR | NM_000372.5 | c.665T>C | p.Ile222Thr | missense_variant | 1/5 | ENST00000263321.6 | |
TYR | XM_011542970.3 | c.665T>C | p.Ile222Thr | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYR | ENST00000263321.6 | c.665T>C | p.Ile222Thr | missense_variant | 1/5 | 1 | NM_000372.5 | P1 | |
TYR | ENST00000526139.1 | n.726T>C | non_coding_transcript_exon_variant | 1/3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.000868 AC: 132AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000176 AC: 44AN: 250588Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135474
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1460208Hom.: 1 Cov.: 33 AF XY: 0.0000675 AC XY: 49AN XY: 726282
GnomAD4 genome AF: 0.000867 AC: 132AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61AN XY: 74440
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 222 of the TYR protein (p.Ile222Thr). This variant is present in population databases (rs34878847, gnomAD 0.3%). This missense change has been observed in individual(s) with oculocutaneous albinism (Invitae). 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: 499705). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 31, 2018 | - - |
Oculocutaneous albinism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Tyrosinase-negative oculocutaneous albinism Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at