rs10010131

Variant names:

Variant summary

Our verdict is The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_Strong

The NM_006005.3(WFS1):c.461-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.639 (AC=96,763) in the gnomAD database across 151,444 control chromosomes, including 31,471 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.912. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31471 hom., cov: 31)

Exomes 𝑓: 0.62 ( 285946 hom. )

Failed GnomAD Quality Control

Consequence

WFS1
NM_006005.3 intron

Scores

Splicing: ADA: 0.00005842

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.421

Publications

211 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: ClinGen, Ambry Genetics, G2P, Orphanet, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Wolfram syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal dominant nonsyndromic hearing loss 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
cataract 41
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Wolfram syndrome 1
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, 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

new If you want to explore the variant's impact on the transcript NM_006005.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 points.

GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.912 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.461-9A>G		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.461-9A>G		intron	N/A	NP_001139325.1	O76024

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WFS1	ENST00000226760.5	TSL:1 MANE Select	c.461-9A>G	intron	N/A	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.461-9A>G	intron	N/A	ENSP00000423337.1	O76024
WFS1	ENST00000852027.1		c.461-9A>G	intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.639

AC:

96669

AN:

151326

Hom.:

31429

Cov.:

show subpopulations

Gnomad AFR

AF:

0.654

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.699

Gnomad ASJ

AF:

0.678

Gnomad EAS

AF:

0.933

Gnomad SAS

AF:

0.711

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.654

Gnomad NFE

AF:

0.600

Gnomad OTH

AF:

0.656

GnomAD2 exomes

AF:

0.662

AC:

164492

AN:

248508

AF XY:

0.659

show subpopulations

Gnomad AFR exome

AF:

0.658

Gnomad AMR exome

AF:

0.748

Gnomad ASJ exome

AF:

0.694

Gnomad EAS exome

AF:

0.931

Gnomad FIN exome

AF:

0.570

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.622

AC:

906540

AN:

1457304

Hom.:

285946

Cov.:

AF XY:

0.624

AC XY:

452378

AN XY:

725028

show subpopulations

African (AFR)

AF:

0.660

AC:

22060

AN:

33418

American (AMR)

AF:

0.744

AC:

33228

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.693

AC:

18098

AN:

26120

East Asian (EAS)

AF:

0.959

AC:

38045

AN:

39692

South Asian (SAS)

AF:

0.702

AC:

60549

AN:

86228

European-Finnish (FIN)

AF:

0.575

AC:

29299

AN:

50922

Middle Eastern (MID)

AF:

0.628

AC:

3623

AN:

5766

European-Non Finnish (NFE)

AF:

0.597

AC:

662684

AN:

1110158

Other (OTH)

AF:

0.646

AC:

38954

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

19139

38278

57417

76556

95695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18212

36424

54636

72848

91060

<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:

0.639

AC:

96763

AN:

151444

Hom.:

31471

Cov.:

AF XY:

0.641

AC XY:

47452

AN XY:

73980

show subpopulations

African (AFR)

AF:

0.654

AC:

27009

AN:

41278

American (AMR)

AF:

0.700

AC:

10670

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

2349

AN:

3464

East Asian (EAS)

AF:

0.934

AC:

4759

AN:

5096

South Asian (SAS)

AF:

0.710

AC:

3407

AN:

4796

European-Finnish (FIN)

AF:

0.571

AC:

5982

AN:

10478

Middle Eastern (MID)

AF:

0.645

AC:

187

AN:

290

European-Non Finnish (NFE)

AF:

0.600

AC:

40662

AN:

67782

Other (OTH)

AF:

0.660

AC:

1389

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1741

3482

5223

6964

8705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.625

Hom.:

61871

Bravo

AF:

0.651

Asia WGS

AF:

0.818

AC:

2846

AN:

3478

EpiCase

AF:

0.605

EpiControl

AF:

0.607

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.985

AC:

120924

AN:

122818

Turkish Variome

AF:

0.648

AC:

4332

AN:

6688

Hom.:

1415

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.929

AC:

8323

AN:

8960

Hom.:

3859

ABraOM SABE-WGS-1171

AF:

0.636

AC:

1489

AN:

2342

Hom.:

486

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (5)

Wolfram syndrome 1 (2)

Autosomal dominant nonsyndromic hearing loss 6 (1)

Type 2 diabetes mellitus (1)

WFS1-Related Spectrum Disorders (1)

Wolfram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.1

(source)

DANN

Benign

0.48

PhyloP100

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000058

dbscSNV1_RF

Benign

0.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over