Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004183.4(BEST1):c.109T>C(p.Leu37Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,613,370 control chromosomes in the GnomAD database, including 145,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 21404 hom., cov: 32)

Exomes 𝑓: 0.38 ( 123599 hom. )

Consequence

BEST1
NM_004183.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: -0.761

Publications

46 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 11-61951915-T-C is Benign according to our data. Variant chr11-61951915-T-C is described in ClinVar as Benign. ClinVar VariationId is 99678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.761 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004183.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BEST1	NM_004183.4	MANE Select	c.109T>C	p.Leu37Leu	synonymous	Exon 2 of 11	NP_004174.1
BEST1	NM_001440571.1		c.109T>C	p.Leu37Leu	synonymous	Exon 2 of 10	NP_001427500.1
BEST1	NM_001440572.1		c.109T>C	p.Leu37Leu	synonymous	Exon 2 of 9	NP_001427501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BEST1	ENST00000378043.9	TSL:1 MANE Select	c.109T>C	p.Leu37Leu	synonymous	Exon 2 of 11	ENSP00000367282.4
BEST1	ENST00000449131.6	TSL:1	c.-29+1488T>C		intron	N/A	ENSP00000399709.2
BEST1	ENST00000524926.5	TSL:2	n.109T>C		non_coding_transcript_exon	Exon 2 of 11	ENSP00000432681.1

Frequencies

GnomAD3 genomes

AF:

0.492

AC:

74763

AN:

152006

Hom.:

21364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.492

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.911

Gnomad SAS

AF:

0.715

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.488

AC:

122451

AN:

251064

AF XY:

0.480

show subpopulations

Gnomad AFR exome

AF:

0.732

Gnomad AMR exome

AF:

0.623

Gnomad ASJ exome

AF:

0.263

Gnomad EAS exome

AF:

0.912

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

AF:

0.380

AC:

555789

AN:

1461246

Hom.:

123599

Cov.:

AF XY:

0.387

AC XY:

281424

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.743

AC:

24873

AN:

33476

American (AMR)

AF:

0.609

AC:

27245

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

7059

AN:

26134

East Asian (EAS)

AF:

0.934

AC:

37072

AN:

39694

South Asian (SAS)

AF:

0.694

AC:

59885

AN:

86244

European-Finnish (FIN)

AF:

0.453

AC:

24028

AN:

52988

Middle Eastern (MID)

AF:

0.330

AC:

1891

AN:

5726

European-Non Finnish (NFE)

AF:

0.314

AC:

348678

AN:

1111878

Other (OTH)

AF:

0.415

AC:

25058

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

19470

38940

58409

77879

97349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11868

23736

35604

47472

59340

<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

AF:

0.492

AC:

74857

AN:

152124

Hom.:

21404

Cov.:

AF XY:

0.504

AC XY:

37507

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.732

AC:

30364

AN:

41490

American (AMR)

AF:

0.493

AC:

7541

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3470

East Asian (EAS)

AF:

0.911

AC:

4722

AN:

5182

South Asian (SAS)

AF:

0.714

AC:

3441

AN:

4822

European-Finnish (FIN)

AF:

0.461

AC:

4878

AN:

10574

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21793

AN:

67974

Other (OTH)

AF:

0.416

AC:

880

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1718

3435

5153

6870

8588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.375

Hom.:

54994

Bravo

AF:

0.503

Asia WGS

AF:

0.768

AC:

2668

AN:

3478

EpiCase

AF:

0.304

EpiControl

AF:

0.299

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (5)

Autosomal dominant vitreoretinochoroidopathy (2)

Vitelliform macular dystrophy 2 (2)

Autosomal recessive bestrophinopathy (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa 50 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

5.9

(source)

DANN

Benign

0.60

PhyloP100

-0.76

Mutation Taster

=99/1

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over