rs71524363

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_006005.3(WFS1):c.9C>T(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,554,850 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 48 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 53 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.02

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-6277464-C-T is Benign according to our data. Variant chr4-6277464-C-T is described in ClinVar as Benign. ClinVar VariationId is 130752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2037/152334) while in subpopulation AFR AF = 0.0458 (1905/41576). AF 95% confidence interval is 0.0441. There are 48 homozygotes in GnomAd4. There are 943 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AD,AR,Unknown gene

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.9C>T	p.Ser3Ser	synonymous	Exon 2 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.9C>T	p.Ser3Ser	synonymous	Exon 2 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.9C>T	p.Ser3Ser	synonymous	Exon 2 of 8	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.9C>T	p.Ser3Ser	synonymous	Exon 2 of 8	ENSP00000423337.1	O76024
WFS1	ENST00000852027.1		c.9C>T	p.Ser3Ser	synonymous	Exon 2 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2022

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00315

AC:

492

AN:

156364

AF XY:

0.00224

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000842

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00143

AC:

2004

AN:

1402516

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

879

AN XY:

692136

show subpopulations

African (AFR)

AF:

0.0482

AC:

1541

AN:

31946

American (AMR)

AF:

0.00301

AC:

109

AN:

36164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

36272

South Asian (SAS)

AF:

0.000214

AC:

AN:

79584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48258

Middle Eastern (MID)

AF:

0.00476

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0000777

AC:

AN:

1081272

Other (OTH)

AF:

0.00389

AC:

226

AN:

58166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0134

AC:

2037

AN:

152334

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

943

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0458

AC:

1905

AN:

41576

American (AMR)

AF:

0.00614

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68032

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

107

214

321

428

535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00574

Hom.:

Bravo

AF:

0.0151

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Autosomal dominant nonsyndromic hearing loss 6 (1)

WFS1-Related Spectrum Disorders (1)

Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

-1.0

PromoterAI

-0.0060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.40

Position offset: 34

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over