NM_004183.4:c.219C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1

The NM_004183.4(BEST1):c.219C>A(p.Ile73Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,614,080 control chromosomes in the GnomAD database, including 31,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2617 hom., cov: 32)

Exomes 𝑓: 0.13 ( 29049 hom. )

Consequence

BEST1
NM_004183.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.434

Publications

51 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: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.13).

BP6

Variant 11-61955173-C-A is Benign according to our data. Variant chr11-61955173-C-A is described in ClinVar as Benign. ClinVar VariationId is 99693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.659 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.219C>A	p.Ile73Ile	synonymous	Exon 3 of 11	NP_004174.1
BEST1	NM_001440571.1		c.219C>A	p.Ile73Ile	synonymous	Exon 3 of 10	NP_001427500.1
BEST1	NM_001440572.1		c.219C>A	p.Ile73Ile	synonymous	Exon 3 of 9	NP_001427501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BEST1	ENST00000378043.9	TSL:1 MANE Select	c.219C>A	p.Ile73Ile	synonymous	Exon 3 of 11	ENSP00000367282.4
BEST1	ENST00000449131.6	TSL:1	c.39C>A	p.Ile13Ile	synonymous	Exon 2 of 9	ENSP00000399709.2
BEST1	ENST00000526988.1	TSL:2	c.-145C>A		5_prime_UTR	Exon 1 of 9	ENSP00000433195.1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18910

AN:

152104

Hom.:

2616

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0878

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.677

Gnomad SAS

AF:

0.531

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0743

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.205

AC:

51573

AN:

251400

AF XY:

0.213

show subpopulations

Gnomad AFR exome

AF:

0.0847

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.0405

Gnomad EAS exome

AF:

0.680

Gnomad FIN exome

AF:

0.0699

Gnomad NFE exome

AF:

0.0767

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.126

AC:

184849

AN:

1461858

Hom.:

29049

Cov.:

AF XY:

0.137

AC XY:

99437

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0831

AC:

2783

AN:

33480

American (AMR)

AF:

0.288

AC:

12885

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0417

AC:

1090

AN:

26136

East Asian (EAS)

AF:

0.749

AC:

29748

AN:

39696

South Asian (SAS)

AF:

0.504

AC:

43477

AN:

86258

European-Finnish (FIN)

AF:

0.0677

AC:

3619

AN:

53418

Middle Eastern (MID)

AF:

0.105

AC:

608

AN:

5768

European-Non Finnish (NFE)

AF:

0.0737

AC:

81970

AN:

1111982

Other (OTH)

AF:

0.144

AC:

8669

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

7890

15779

23669

31558

39448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3618

7236

10854

14472

18090

<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:

0.124

AC:

18915

AN:

152222

Hom.:

2617

Cov.:

AF XY:

0.136

AC XY:

10101

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0877

AC:

3646

AN:

41554

American (AMR)

AF:

0.197

AC:

3005

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3470

East Asian (EAS)

AF:

0.678

AC:

3488

AN:

5148

South Asian (SAS)

AF:

0.530

AC:

2557

AN:

4824

European-Finnish (FIN)

AF:

0.0692

AC:

734

AN:

10612

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0743

AC:

5054

AN:

68016

Other (OTH)

AF:

0.116

AC:

245

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

720

1440

2159

2879

3599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.0995

Hom.:

6449

Bravo

AF:

0.131

Asia WGS

AF:

0.530

AC:

1839

AN:

3478

EpiCase

AF:

0.0724

EpiControl

AF:

0.0742

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Vitelliform macular dystrophy 2 (2)

Autosomal dominant vitreoretinochoroidopathy (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Vitelliform macular dystrophy 2;C2750789:Retinitis pigmentosa 50;C3888099:Autosomal dominant vitreoretinochoroidopathy;C3888198:Autosomal recessive bestrophinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-0.43

PromoterAI

0.24

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over