rs267606678

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_004183.4(BEST1):c.418C>G(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 Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BEST1
NM_004183.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.23

Publications

14 publications found

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]

BEST1 Gene-Disease associations (from GenCC):

autosomal dominant vitreoretinochoroidopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
inherited retinal dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
vitelliform macular dystrophy 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
autosomal recessive bestrophinopathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa 50
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
adult-onset foveomacular vitelliform dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
MRCS syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BEST1 links:

LOC107984334 (HGNC:):

LOC107984334 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004183.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-61955889-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3249898.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 0.61695 (below the threshold of 3.09). Trascript score misZ: 0.88358 (below the threshold of 3.09). GenCC associations: The gene is linked to vitelliform macular dystrophy 2, MRCS syndrome, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, retinitis pigmentosa, retinitis pigmentosa 50, inherited retinal dystrophy, adult-onset foveomacular vitelliform dystrophy, nanophthalmia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 11-61955888-C-G is Pathogenic according to our data. Variant chr11-61955888-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2750.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST1	NM_004183.4 link	c.418C>G	p.Leu140Val	missense_variant	Exon 4 of 11	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9 link	c.418C>G	p.Leu140Val	missense_variant	Exon 4 of 11	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000333

AC:

AN:

150144

AF XY:

0.0000502

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1398186

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

689664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35790

South Asian (SAS)

AF:

0.000240

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078894

Other (OTH)

AF:

0.0000172

AC:

AN:

57992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Oct 14, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs267606678, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of autosomal recessive bestrophinopathy (PMID: 19853238, 32239196). ClinVar contains an entry for this variant (Variation ID: 2750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BEST1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BEST1 function (PMID: 19853238, 21330666, 24560797). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 50

Pathogenic:1

Nov 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;D;.;D

Eigen

Benign

-0.025

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.;.

PhyloP100

1.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;T

Polyphen

1.0

D;.;D;B

Vest4

0.71

MutPred

0.80

Gain of sheet (P = 0.0827);.;.;.;

MVP

0.96

MPC

0.92

ClinPred

0.44

GERP RS

3.3

Varity_R

0.68

gMVP

0.84

Mutation Taster

=2/98

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over