4-6302247-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006005.3(WFS1):c.2452C>T(p.Arg818Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,605,064 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R818H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 35)

Exomes 𝑓: 0.0052 ( 29 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: 1.47

Publications

34 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):

Wolfram-like syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017019987).

BP6

Variant 4-6302247-C-T is Benign according to our data. Variant chr4-6302247-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130748.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00408 (622/152338) while in subpopulation SAS AF = 0.00869 (42/4832). AF 95% confidence interval is 0.00661. There are 6 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.2452C>T	p.Arg818Cys	missense	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.2452C>T	p.Arg818Cys	missense	Exon 8 of 8	NP_001139325.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WFS1	ENST00000226760.5	TSL:1 MANE Select	c.2452C>T	p.Arg818Cys	missense	Exon 8 of 8	ENSP00000226760.1
WFS1	ENST00000503569.5	TSL:1	c.2452C>T	p.Arg818Cys	missense	Exon 8 of 8	ENSP00000423337.1
WFS1	ENST00000852027.1		c.2545C>T	p.Arg849Cys	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

623

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.0279

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00868

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00560

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00502

AC:

1243

AN:

247384

AF XY:

0.00550

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0284

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00188

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.00548

GnomAD4 exome

AF:

0.00517

AC:

7513

AN:

1452726

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

3870

AN XY:

721260

show subpopulations

African (AFR)

AF:

0.000510

AC:

AN:

33326

American (AMR)

AF:

0.00159

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

729

AN:

25906

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39536

South Asian (SAS)

AF:

0.00759

AC:

652

AN:

85918

European-Finnish (FIN)

AF:

0.00181

AC:

AN:

51510

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00500

AC:

5530

AN:

1106254

Other (OTH)

AF:

0.00592

AC:

355

AN:

60012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

493

986

1478

1971

2464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00408

AC:

622

AN:

152338

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41578

American (AMR)

AF:

0.00242

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00869

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00216

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00560

AC:

381

AN:

68032

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00598

Hom.:

Bravo

AF:

0.00404

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00479

AC:

581

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (4)

Autosomal dominant nonsyndromic hearing loss 6 (1)

Monogenic diabetes (1)

WFS1-Related Spectrum Disorders (1)

Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.017

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.2

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.76

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.90

MVP

0.99

ClinPred

0.029

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.66

Mutation Taster

=74/26

polymorphism

(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