4-6301849-G-A

Position:

chr4-6301849-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_006005.3(WFS1):c.2054G>A(p.Arg685His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,612,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R685P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1

Conservation

PhyloP100: 7.21

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:

WFS1 (HGNC:):

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301849-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2054G>A	p.Arg685His	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.2054G>A	p.Arg685His	missense_variant	8/8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2054G>A	p.Arg685His	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000176

AC:

AN:

250084

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000164

AC:

239

AN:

1460530

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000575

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000138

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000150

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2024	Identified in a patient with childhood onset non-ketotic diabetes in published literature, inherited from her mother with adult onset diabetes; they also both carried a variant in the RFX6 gene (PMID: 25048417); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25048417) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2018	- -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Moderate, PM5_Moderate, PP3_Supporting -

Wolfram-like syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.10

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.80

P;P

Vest4

0.61

MVP

1.0

ClinPred

0.075

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.73

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