11-61951814-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_004183.4(BEST1):​c.8T>A​(p.Ile3Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BEST1
NM_004183.4 missense

Scores

14
2
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.90
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PM1
In a topological_domain Cytoplasmic (size 24) in uniprot entity BEST1_HUMAN there are 59 pathogenic changes around while only 0 benign (100%) in NM_004183.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
Variant 11-61951814-T-A is Pathogenic according to our data. Variant chr11-61951814-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1503600.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-61951814-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BEST1NM_004183.4 linkuse as main transcriptc.8T>A p.Ile3Asn missense_variant 2/11 ENST00000378043.9 NP_004174.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BEST1ENST00000378043.9 linkuse as main transcriptc.8T>A p.Ile3Asn missense_variant 2/111 NM_004183.4 ENSP00000367282 P1O76090-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 07, 2023This missense change has been observed in individuals with autosomal dominant BEST1-related conditions (PMID: 26099059; Invitae). ClinVar contains an entry for this variant (Variation ID: 1503600). 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. This variant disrupts the p.Ile3 amino acid residue in BEST1. Other variant(s) that disrupt this residue have been observed in individuals with BEST1-related conditions (PMID: 19357557), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 3 of the BEST1 protein (p.Ile3Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.84
D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
T
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PROVEAN
Pathogenic
-5.4
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.96
D
Vest4
0.86
MutPred
0.82
Gain of disorder (P = 0.0149);
MVP
0.99
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs907161461; hg19: chr11-61719286; API