rs4688989

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006005.3(WFS1):c.316-120T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,455,408 control chromosomes in the GnomAD database, including 291,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33393 hom., cov: 34)

Exomes 𝑓: 0.62 ( 257944 hom. )

Consequence

WFS1
NM_006005.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.73

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 4-6288867-T-C is Benign according to our data. Variant chr4-6288867-T-C is described in ClinVar as Benign. ClinVar VariationId is 1292284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 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.316-120T>C		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.316-120T>C		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.316-120T>C	intron	N/A	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.316-120T>C	intron	N/A	ENSP00000423337.1	O76024
WFS1	ENST00000852027.1		c.316-120T>C	intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.655

AC:

99615

AN:

152000

Hom.:

33350

Cov.:

show subpopulations

Gnomad AFR

AF:

0.707

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.707

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.942

Gnomad SAS

AF:

0.710

Gnomad FIN

AF:

0.574

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.601

Gnomad OTH

AF:

0.669

GnomAD4 exome

AF:

0.625

AC:

814156

AN:

1303290

Hom.:

257944

Cov.:

AF XY:

0.627

AC XY:

405918

AN XY:

647812

show subpopulations

African (AFR)

AF:

0.715

AC:

21318

AN:

29806

American (AMR)

AF:

0.742

AC:

26415

AN:

35594

Ashkenazi Jewish (ASJ)

AF:

0.694

AC:

17012

AN:

24506

East Asian (EAS)

AF:

0.965

AC:

34066

AN:

35308

South Asian (SAS)

AF:

0.700

AC:

53633

AN:

76650

European-Finnish (FIN)

AF:

0.577

AC:

27549

AN:

47704

Middle Eastern (MID)

AF:

0.639

AC:

2679

AN:

4190

European-Non Finnish (NFE)

AF:

0.599

AC:

595648

AN:

994706

Other (OTH)

AF:

0.654

AC:

35836

AN:

54826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

15558

31116

46675

62233

77791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16082

32164

48246

64328

80410

<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:

0.656

AC:

99717

AN:

152118

Hom.:

33393

Cov.:

AF XY:

0.658

AC XY:

48909

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.707

AC:

29339

AN:

41498

American (AMR)

AF:

0.707

AC:

10821

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

2364

AN:

3472

East Asian (EAS)

AF:

0.943

AC:

4873

AN:

5168

South Asian (SAS)

AF:

0.710

AC:

3420

AN:

4818

European-Finnish (FIN)

AF:

0.574

AC:

6069

AN:

10570

Middle Eastern (MID)

AF:

0.656

AC:

193

AN:

294

European-Non Finnish (NFE)

AF:

0.601

AC:

40864

AN:

67982

Other (OTH)

AF:

0.672

AC:

1418

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1781

3562

5342

7123

8904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<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:

0.626

Hom.:

3695

Bravo

AF:

0.668

Asia WGS

AF:

0.825

AC:

2869

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.40

(source)

DANN

Benign

0.52

PhyloP100

-2.7

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