11-61959917-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS1_ModeratePM1PP3PP5BS2_Supporting
The ENST00000378043.9(BEST1):āc.974T>Cā(p.Met325Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,668 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
ENST00000378043.9 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BEST1 | NM_004183.4 | c.974T>C | p.Met325Thr | missense_variant | 9/11 | ENST00000378043.9 | NP_004174.1 | |
LOC107984334 | XR_001748245.2 | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BEST1 | ENST00000378043.9 | c.974T>C | p.Met325Thr | missense_variant | 9/11 | 1 | NM_004183.4 | ENSP00000367282 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000480 AC: 12AN: 249818Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135114
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461448Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726962
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74376
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 14, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BEST1 function (PMID: 21330666, 24560797). 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 BEST1 protein function. ClinVar contains an entry for this variant (Variation ID: 1065753). This missense change has been observed in individual(s) with autosomal recessive bestrophinopathy (PMID: 18179881). 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. This variant is present in population databases (rs368387447, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 325 of the BEST1 protein (p.Met325Thr). - |
BEST1-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2024 | The BEST1 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in the compound heterozygous state in individuals with autosomal recessive Bestrophinopathy (Burgess et al. 2008. PubMed ID: 18179881). The variant has been shown to impact protein localization (Figure S3, Johnson et al. 2014. PubMed ID: 24560797) and reduces chloride channel activity (Davidson et al. 2011. PubMed ID: 21330666). To our knowledge, this variant has not been reported in association with autosomal dominant disease. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. - |
Vitelliform macular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The BEST1 c.974T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at