rs121918285
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PP5_ModerateBS2_Supporting
The NM_004183.4(BEST1):āc.87C>Gā(p.Tyr29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
BEST1
NM_004183.4 stop_gained
NM_004183.4 stop_gained
Scores
3
4
Clinical Significance
Conservation
PhyloP100: 1.20
Genes affected
BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 433 pathogenic variants in the truncated region.
PP5
Variant 11-61951893-C-G is Pathogenic according to our data. Variant chr11-61951893-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-61951893-C-G is described in Lovd as [Likely_pathogenic].
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BEST1 | NM_004183.4 | c.87C>G | p.Tyr29* | stop_gained | 2/11 | ENST00000378043.9 | NP_004174.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BEST1 | ENST00000378043.9 | c.87C>G | p.Tyr29* | stop_gained | 2/11 | 1 | NM_004183.4 | ENSP00000367282.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250918Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135690
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461118Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 726914
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74386
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Vitelliform macular dystrophy 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change creates a premature translational stop signal (p.Tyr29*) in the BEST1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BEST1 are known to be pathogenic (PMID: 21825197). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive bestrophinopathy (PMID: 16754206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2730). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at