chr4-6300818-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_006005.3(WFS1):c.1023C>T(p.Phe341Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,613,996 control chromosomes in the GnomAD database, including 4,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 303 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4075 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.550

Publications

15 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.146).

BP6

Variant 4-6300818-C-T is Benign according to our data. Variant chr4-6300818-C-T is described in ClinVar as Benign. ClinVar VariationId is 45428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0726 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.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1023C>T	p.Phe341Phe	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.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
WFS1	ENST00000503569.5	TSL:1	c.1023C>T	p.Phe341Phe	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
WFS1	ENST00000673642.1		c.682C>T	p.Arg228Cys	missense	Exon 7 of 7	ENSP00000501242.1	A0A669KBF0

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7581

AN:

152108

Hom.:

304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0631

Gnomad FIN

AF:

0.0236

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0743

Gnomad OTH

AF:

0.0537

GnomAD2 exomes

AF:

0.0542

AC:

13625

AN:

251454

AF XY:

0.0568

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0937

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0284

Gnomad NFE exome

AF:

0.0742

Gnomad OTH exome

AF:

0.0624

GnomAD4 exome

AF:

0.0703

AC:

102751

AN:

1461770

Hom.:

4075

Cov.:

AF XY:

0.0704

AC XY:

51173

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0129

AC:

431

AN:

33478

American (AMR)

AF:

0.0349

AC:

1560

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0938

AC:

2452

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39696

South Asian (SAS)

AF:

0.0629

AC:

5429

AN:

86256

European-Finnish (FIN)

AF:

0.0296

AC:

1582

AN:

53418

Middle Eastern (MID)

AF:

0.123

AC:

712

AN:

5768

European-Non Finnish (NFE)

AF:

0.0779

AC:

86646

AN:

1111902

Other (OTH)

AF:

0.0650

AC:

3924

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

7103

14205

21308

28410

35513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3202

6404

9606

12808

16010

<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:

0.0498

AC:

7581

AN:

152226

Hom.:

303

Cov.:

AF XY:

0.0472

AC XY:

3512

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0135

AC:

560

AN:

41546

American (AMR)

AF:

0.0482

AC:

738

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

358

AN:

3468

East Asian (EAS)

AF:

0.00136

AC:

AN:

5166

South Asian (SAS)

AF:

0.0634

AC:

305

AN:

4812

European-Finnish (FIN)

AF:

0.0236

AC:

251

AN:

10614

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0743

AC:

5052

AN:

68014

Other (OTH)

AF:

0.0531

AC:

112

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

378

756

1133

1511

1889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0672

Hom.:

218

Bravo

AF:

0.0507

Asia WGS

AF:

0.0230

AC:

AN:

3476

EpiCase

AF:

0.0792

EpiControl

AF:

0.0785

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

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

-0.47

CADD

Benign

4.1

(source)

DANN

Benign

0.74

PhyloP100

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

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

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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