rs147834269

Positions:

chr4-6302004-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_006005.3(WFS1):c.2209G>A(p.Glu737Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,612,666 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 3 hom., cov: 34)

Exomes 𝑓: 0.00098 ( 23 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 9.39

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 -11 ACMG points.

PM1

In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3

BP4

Computational evidence support a benign effect (MetaRNN=0.017220378).

BP6

Variant 4-6302004-G-A is Benign according to our data. Variant chr4-6302004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143132.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=2}. Variant chr4-6302004-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00098 (1431/1460344) while in subpopulation EAS AF= 0.0312 (1238/39684). AF 95% confidence interval is 0.0298. There are 23 homozygotes in gnomad4_exome. There are 705 alleles in male gnomad4_exome subpopulation. Median coverage is 97. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2209G>A	p.Glu737Lys	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.2209G>A	p.Glu737Lys	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2209G>A	p.Glu737Lys	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1911C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000732

AC:

180

AN:

245920

Hom.:

AF XY:

0.000611

AC XY:

AN XY:

134112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00171

Gnomad EAS exome

AF:

0.00744

Gnomad SAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.000664

GnomAD4 exome

AF:

0.000980

AC:

1431

AN:

1460344

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

705

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.0312

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000827

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000479

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.0112

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000467

AC:

ExAC

AF:

0.000891

AC:

108

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	This variant is associated with the following publications: (PMID: 22938506, 11161832, 10760554, 29728875, 29529044, 30872718, 16408729, 11317350, 27212798, 30245029, 31264968) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2023	- -

Wolfram syndrome 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2014

Glu737Lys in exon 8 of WFS1: This variant is not expected to have clinical signi ficance because it has been identified in 4/8568 of European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs147834269) and in 6.7% (12/178) of Japanese chromosomes by the 1000 Genomes Project (dbSNP rs147834269). It is reported as a benign variant in 3 publication s (Ohtsuki 2000, Gomez-Zaera 2001, Baek 2012). -

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. -

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

Benign

0.18

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.56

P;P

Vest4

0.71

MVP

0.99

ClinPred

0.12

GERP RS

5.5

Varity_R

0.60

gMVP

0.90

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