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):ā€‹c.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

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.000023 ( 0 hom. )

Consequence

BEST1
ENST00000378043.9 missense

Scores

9
4
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.19
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]
FTH1 (HGNC:3976): (ferritin heavy chain 1) This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS1
Transcript ENST00000378043.9 (BEST1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000378043.9
PP3
MetaRNN computational evidence supports a deleterious effect, 0.776
PP5
Variant 11-61959917-T-C is Pathogenic according to our data. Variant chr11-61959917-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1065753.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr11-61959917-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-61959917-T-C is described in Lovd as [Likely_pathogenic].
BS2
High AC in GnomAd4 at 12 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
BEST1NM_004183.4 linkuse as main transcriptc.974T>C p.Met325Thr missense_variant 9/11 ENST00000378043.9 NP_004174.1
LOC107984334XR_001748245.2 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BEST1ENST00000378043.9 linkuse as main transcriptc.974T>C p.Met325Thr missense_variant 9/111 NM_004183.4 ENSP00000367282 P1O76090-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000480
AC:
12
AN:
249818
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135114
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461448
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
726962
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000655
Hom.:
0
Bravo
AF:
0.000102
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 14, 2022For 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 providedclinical testingPreventionGenetics, part of Exact SciencesSep 10, 2024The 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 submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.54
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.074
T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.32
T
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PROVEAN
Benign
1.5
N
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.018
D
Polyphen
1.0
D
Vest4
0.86
MVP
0.95
ClinPred
0.60
D
GERP RS
3.6

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: rs368387447; hg19: chr11-61727389; API