rs1046314

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_006005.3(WFS1):c.2433G>A(p.Lys811Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,608,966 control chromosomes in the GnomAD database, including 298,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 27101 hom., cov: 34)

Exomes 𝑓: 0.61 ( 271066 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.19

Publications

56 publications found

Variant links:

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

WFS1 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Wolfram-like syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
Wolfram syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
autosomal dominant nonsyndromic hearing loss 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cataract 41
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Wolfram syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
type 2 diabetes mellitus
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

WFS1 links:

ENSG00000286176 (HGNC:58722):

ENSG00000286176 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=-0.81).

BP6

Variant 4-6302228-G-A is Benign according to our data. Variant chr4-6302228-G-A is described in ClinVar as Benign. ClinVar VariationId is 45455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.2433G>A	p.Lys811Lys	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.2433G>A	p.Lys811Lys	synonymous	Exon 8 of 8	NP_001139325.1	O76024

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WFS1	ENST00000226760.5	TSL:1 MANE Select	c.2433G>A	p.Lys811Lys	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.2433G>A	p.Lys811Lys	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
WFS1	ENST00000852027.1		c.2526G>A	p.Lys842Lys	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.587

AC:

89312

AN:

152030

Hom.:

27083

Cov.:

show subpopulations

Gnomad AFR

AF:

0.503

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.933

Gnomad SAS

AF:

0.642

Gnomad FIN

AF:

0.562

Gnomad MID

AF:

0.625

Gnomad NFE

AF:

0.592

Gnomad OTH

AF:

0.616

GnomAD2 exomes

AF:

0.637

AC:

157797

AN:

247650

AF XY:

0.635

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.676

Gnomad EAS exome

AF:

0.931

Gnomad FIN exome

AF:

0.568

Gnomad NFE exome

AF:

0.588

Gnomad OTH exome

AF:

0.633

GnomAD4 exome

AF:

0.606

AC:

882669

AN:

1456816

Hom.:

271066

Cov.:

101

AF XY:

0.607

AC XY:

439418

AN XY:

724210

show subpopulations

African (AFR)

AF:

0.502

AC:

16794

AN:

33426

American (AMR)

AF:

0.728

AC:

32489

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

17604

AN:

26014

East Asian (EAS)

AF:

0.958

AC:

37960

AN:

39644

South Asian (SAS)

AF:

0.634

AC:

54535

AN:

86054

European-Finnish (FIN)

AF:

0.568

AC:

29280

AN:

51546

Middle Eastern (MID)

AF:

0.591

AC:

3401

AN:

5758

European-Non Finnish (NFE)

AF:

0.589

AC:

653164

AN:

1109532

Other (OTH)

AF:

0.622

AC:

37442

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

23557

47114

70672

94229

117786

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18078

36156

54234

72312

90390

<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:

0.587

AC:

89362

AN:

152150

Hom.:

27101

Cov.:

AF XY:

0.589

AC XY:

43796

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.502

AC:

20856

AN:

41506

American (AMR)

AF:

0.669

AC:

10241

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

2294

AN:

3472

East Asian (EAS)

AF:

0.933

AC:

4822

AN:

5166

South Asian (SAS)

AF:

0.643

AC:

3102

AN:

4826

European-Finnish (FIN)

AF:

0.562

AC:

5952

AN:

10600

Middle Eastern (MID)

AF:

0.616

AC:

180

AN:

292

European-Non Finnish (NFE)

AF:

0.592

AC:

40256

AN:

67970

Other (OTH)

AF:

0.618

AC:

1305

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1871

3742

5612

7483

9354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.598

Hom.:

66584

Bravo

AF:

0.593

Asia WGS

AF:

0.754

AC:

2624

AN:

3478

EpiCase

AF:

0.593

EpiControl

AF:

0.600

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (4)

Autosomal dominant nonsyndromic hearing loss 6 (1)

Diabetes mellitus (1)

Sensorineural hearing loss disorder (1)

WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.3

(source)

DANN

Benign

0.62

PhyloP100

1.2

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over