Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004183.4(BEST1):c.1557C>T(p.Ser519Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,614,032 control chromosomes in the GnomAD database, including 36,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2526 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33535 hom. )

Consequence

BEST1
NM_004183.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -1.42

Publications

18 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 links:

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]

FTH1 Gene-Disease associations (from GenCC):

hemochromatosis type 5
Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
neurodegeneration with brain iron accumulation 9
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

FTH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 11-61962711-C-T is Benign according to our data. Variant chr11-61962711-C-T is described in ClinVar as Benign. ClinVar VariationId is 99680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.42 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 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.1557C>T	p.Ser519Ser	synonymous	Exon 10 of 11	NP_004174.1
BEST1	NM_001440571.1		c.1557C>T	p.Ser519Ser	synonymous	Exon 10 of 10	NP_001427500.1
BEST1	NM_001440572.1		c.1476C>T	p.Ser492Ser	synonymous	Exon 9 of 9	NP_001427501.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BEST1	ENST00000378043.9	TSL:1 MANE Select	c.1557C>T	p.Ser519Ser	synonymous	Exon 10 of 11	ENSP00000367282.4
BEST1	ENST00000449131.6	TSL:1	c.1377C>T	p.Ser459Ser	synonymous	Exon 9 of 9	ENSP00000399709.2
BEST1	ENST00000524877.5	TSL:2	n.5399C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes

AF:

0.159

AC:

24202

AN:

152090

Hom.:

2530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0453

Gnomad AMI

AF:

0.395

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.163

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.228

Gnomad OTH

AF:

0.185

GnomAD2 exomes

AF:

0.175

AC:

43944

AN:

251328

AF XY:

0.185

show subpopulations

Gnomad AFR exome

AF:

0.0431

Gnomad AMR exome

AF:

0.108

Gnomad ASJ exome

AF:

0.307

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.223

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.206

AC:

301232

AN:

1461824

Hom.:

33535

Cov.:

AF XY:

0.208

AC XY:

151502

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0404

AC:

1352

AN:

33480

American (AMR)

AF:

0.113

AC:

5053

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

7945

AN:

26136

East Asian (EAS)

AF:

0.00116

AC:

AN:

39670

South Asian (SAS)

AF:

0.207

AC:

17848

AN:

86254

European-Finnish (FIN)

AF:

0.162

AC:

8671

AN:

53410

Middle Eastern (MID)

AF:

0.243

AC:

1402

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

247141

AN:

1111988

Other (OTH)

AF:

0.195

AC:

11774

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16417

32835

49252

65670

82087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8266

16532

24798

33064

41330

<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:

0.159

AC:

24195

AN:

152208

Hom.:

2526

Cov.:

AF XY:

0.157

AC XY:

11707

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0453

AC:

1881

AN:

41540

American (AMR)

AF:

0.148

AC:

2256

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1044

AN:

3466

East Asian (EAS)

AF:

0.00328

AC:

AN:

5182

South Asian (SAS)

AF:

0.200

AC:

965

AN:

4822

European-Finnish (FIN)

AF:

0.163

AC:

1722

AN:

10592

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.228

AC:

15479

AN:

67998

Other (OTH)

AF:

0.184

AC:

388

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

995

1990

2985

3980

4975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.201

Hom.:

2981

Bravo

AF:

0.152

Asia WGS

AF:

0.0820

AC:

288

AN:

3478

EpiCase

AF:

0.237

EpiControl

AF:

0.236

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (4)

Autosomal dominant vitreoretinochoroidopathy (1)

Iron Overload (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Retinitis Pigmentosa, Recessive (1)

Vitelliform macular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.32

(source)

DANN

Benign

0.60

PhyloP100

-1.4

Mutation Taster

=100/0

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.

rs1800008

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