chr4-6302247-C-T

Position:

chr4-6302247-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R818H) has been classified as Uncertain significance.

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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_006005.3

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 id is 130748.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=6}. Variant chr4-6302247-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2452C>T	p.Arg818Cys	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.2452C>T	p.Arg818Cys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2452C>T	p.Arg818Cys	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1668G>A		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.00502

AC:

1243

AN:

247384

Hom.:

AF XY:

0.00550

AC XY:

738

AN XY:

134082

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 SAS exome

AF:

0.00758

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

Gnomad4 AFR exome

AF:

0.000510

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.0281

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00759

Gnomad4 FIN exome

AF:

0.00181

Gnomad4 NFE exome

AF:

0.00500

Gnomad4 OTH exome

AF:

0.00592

GnomAD4 genome

AF:

0.00408

AC:

622

AN:

152338

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.0279

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00560

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00633

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:7

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2022	BA1, BS1, PP3 -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	WFS1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2019	Incidentally identified in the diabetic father of a proband with Wolfram syndrome, though the proband had not inherited this variant (Smith et al., 2004).; Identified in the heterozygous state in another individual who was also homozygous for an in-frame insertion of three amino acids in the WFS1 gene (Smith et al., 2004).; Reported on both WFS1 alleles in an individual with Wolfram syndrome (Domenech et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27151922, 11161832, 11317350, 23595122, 12605098, 23429432, 15277431, 27013921, 11244483, 28432734, 15151504, 29511501, 30245029, 29563951, 31638168) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2015	p.Arg818Cys in exon 8 of WFS1: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (129/15874) of South Asian chro mosomes including 1 homozygote by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs35932623). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 31, 2015

ACMG Criteria: PP3, PP5 (PMID:21446023), BS2, BP6 -

WFS1-Related Spectrum Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Wolfram syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

.;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over