4-42893597-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong
The NM_001080476.3(GRXCR1):āc.331T>Cā(p.Tyr111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,613,570 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001080476.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRXCR1 | NM_001080476.3 | c.331T>C | p.Tyr111His | missense_variant | 1/4 | ENST00000399770.3 | NP_001073945.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRXCR1 | ENST00000399770.3 | c.331T>C | p.Tyr111His | missense_variant | 1/4 | 1 | NM_001080476.3 | ENSP00000382670 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152102Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000121 AC: 30AN: 248592Hom.: 0 AF XY: 0.0000890 AC XY: 12AN XY: 134854
GnomAD4 exome AF: 0.000260 AC: 380AN: 1461468Hom.: 0 Cov.: 33 AF XY: 0.000241 AC XY: 175AN XY: 727046
GnomAD4 genome AF: 0.000164 AC: 25AN: 152102Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74288
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 06, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 19, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 111 of the GRXCR1 protein (p.Tyr111His). This variant is present in population databases (rs201002003, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GRXCR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 348818). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 18, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Tyr111His var iant in GRXCR1 has not been previously reported in individuals with hearing loss . It has been identified in 27/125910 European chromosomes by the genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs201002003); ho wever this frequency is not high enough to rule out a pathogenic role. The varia nt has also been reported in ClinVar (Variation ID: 348818). The Tyrosine (Tyr) at position 111 is conserved through mammals, but is not highly conserved in evo lutionary distant species with >30 species carry a Histidine (His) at this posit ion, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest the variant may not impact the protein. In summary, while the clinical significance of the p.Tyr111His variant is uncertain, these data suggest that it is more likely to be benign. - |
Autosomal recessive nonsyndromic hearing loss 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at