4-6301738-G-T

Position:

chr4-6301738-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006005.3(WFS1):c.1943G>T(p.Trp648Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.04

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1943G>T	p.Trp648Leu	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.1943G>T	p.Trp648Leu	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.1943G>T	p.Trp648Leu	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251222

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 17, 2013

The Trp648Leu variant in WFS1 has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) provide inconsistent predictions on the impact of the variant on the protein. Therefore, additional data is needed to determine the clinical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.1943G>T (p.W648L) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to T substitution at nucleotide position 1943, causing the tryptophan (W) at amino acid position 648 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 45444). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. This variant is present in population databases (rs150465110, gnomAD 0.002%). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 648 of the WFS1 protein (p.Trp648Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

.;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.056

T;T

Polyphen

0.29

B;B

Vest4

0.78

MutPred

0.50

Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

1.0

ClinPred

0.72

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.88

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