rs267606678
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM5PP3_ModeratePP5BS2_Supporting
The NM_004183.4(BEST1):āc.418C>Gā(p.Leu140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,398,186 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L140R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004183.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BEST1 | NM_004183.4 | c.418C>G | p.Leu140Val | missense_variant | 4/11 | ENST00000378043.9 | NP_004174.1 | |
LOC107984334 | XR_001748245.2 | n.2806G>C | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BEST1 | ENST00000378043.9 | c.418C>G | p.Leu140Val | missense_variant | 4/11 | 1 | NM_004183.4 | ENSP00000367282 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000333 AC: 5AN: 150144Hom.: 0 AF XY: 0.0000502 AC XY: 4AN XY: 79724
GnomAD4 exome AF: 0.0000143 AC: 20AN: 1398186Hom.: 0 Cov.: 37 AF XY: 0.0000217 AC XY: 15AN XY: 689664
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This variant is present in population databases (rs267606678, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BEST1 function (PMID: 19853238, 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: 2750). This missense change has been observed in individuals with clinical features of autosomal recessive bestrophinopathy (PMID: 19853238, 32239196). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 140 of the BEST1 protein (p.Leu140Val). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2016 | - - |
Retinitis pigmentosa 50 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at