rs1800995
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM5PP5_Very_Strong
The NM_004183.4(BEST1):c.436_437delinsAA(p.Ala146Lys) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146S) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
BEST1
NM_004183.4 missense
NM_004183.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.66
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PS1
?
Transcript NM_004183.4 (BEST1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004183.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-61955906-G-T is described in Lovd as [Likely_pathogenic].
PP5
?
Variant 11-61955906-GC-AA is Pathogenic according to our data. Variant chr11-61955906-GC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 2736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BEST1 | NM_004183.4 | c.436_437delinsAA | p.Ala146Lys | missense_variant | 4/11 | ENST00000378043.9 | |
LOC107984334 | XR_001748245.2 | n.2787_2788delinsTT | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BEST1 | ENST00000378043.9 | c.436_437delinsAA | p.Ala146Lys | missense_variant | 4/11 | 1 | NM_004183.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2015 | The c.436_437delGCinsAA mutation in the BEST1 gene, which leads to substitution of Alanine 146 with a Lysine residue, has been reported previously in association with Best disease (Allikmets et al., 1999). We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BEST1 function (PMID: 17898294, 23139242). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2736). This missense change has been observed in individuals with autosomal dominant Best disease (PMID: 10453731, 10737974, 11713080, 23139242). This variant is present in population databases (rs1800995, gnomAD 0.0007%). This sequence change replaces alanine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 146 of the BEST1 protein (p.Ala146Lys). - |
Vitelliform macular dystrophy 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at