chr4-6301392-C-T

Position:

chr4-6301392-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP3BP4_Moderate

The NM_006005.3(WFS1):c.1597C>T(p.Pro533Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,612,448 control chromosomes in the GnomAD database, including 2 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 0.00096 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:12B:1

Conservation

PhyloP100: 6.88

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 1 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity WFS1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006005.3

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Dann, Eigen, M_CAP, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.13240439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1597C>T	p.Pro533Ser	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.1597C>T	p.Pro533Ser	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.1597C>T	p.Pro533Ser	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.000965

AC:

147

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.000327

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:

0.00137

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000747

AC:

187

AN:

250430

Hom.:

AF XY:

0.000738

AC XY:

100

AN XY:

135482

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000483

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00113

AC:

1647

AN:

1460068

Hom.:

Cov.:

100

AF XY:

0.00107

AC XY:

776

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000116

Gnomad4 NFE exome

AF:

0.00141

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152380

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 533 of the WFS1 protein (p.Pro533Ser). This variant is present in population databases (rs146132083, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wolfram syndrome (PMID: 26875006, 28432734, 31264968, 33841295, 35469785). ClinVar contains an entry for this variant (Variation ID: 137914). 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) performed at Invitae indicates that this missense variant is expected to disrupt WFS1 protein function with a positive predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	WFS1: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2024	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: 12955714, 11920861, 28432734, 20738327, 26435059, 31264968, 24875298, 33841295, 34746052, 30180840, 31765440, 35469785, 26875006, 35472603, OrssaudC2024[preprint]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 20, 2023	PM3_Strong, BS1, PP3 -

WFS1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The WFS1 c.1597C>T variant is predicted to result in the amino acid substitution p.Pro533Ser. This variant has been reported along with a second WFS1 variant in individuals with Wolfram syndrome and/or optic atrophy (Table S1 in Majander et al. 2016. PubMed ID: 26875006; Table S2 in Charif et al. 2021. PubMed ID: 33841295). Additionally, here at PreventionGenetics, this variant has been detected in trans with a pathogenic variant in an individual undergoing testing for optic atrophy (internal data). This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD, indicating this variant is relatively common. This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Pro533Ser var iant in WFS1 has been reported in 1 individual with Wolfram Syndrome and 1 indiv idual with post-lingual mild sensorineural hearing loss, but a second variant in WFS1 was not identified in either case (Prince 2012, LMM data). This variant wa s identified in an unaffected parent, suggesting that it would not cause the dom inant form of disease. This variant has also been identified in 0.12% (82/67552) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadi nstitute.org; dbSNP rs146132083), though this frequency is not high enough to ru le out a pathogenic role. Computational prediction tools and conservation analys is suggest that the Pro533Ser variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Pro533Ser variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP c riteria applied: BS1_Supporting. -

WFS1-Related Spectrum Disorders

Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2022

The c.1597C>T (p.P533S) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a C to T substitution at nucleotide position 1597, causing the proline (P) at amino acid position 533 to be replaced by a serine (S). 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

Jun 05, 2024

- -

Optic atrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Wolfram syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 19, 2024

- -

Autosomal dominant nonsyndromic hearing loss 6

Uncertain:1

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Monogenic diabetes

Benign:1

Likely benign, flagged submission

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 12, 2018

ACMG criteria: PP3 (10 predictors), BS2 ( 8 controls and 5 cases in T2DM), BP6 (GeneDx says benign), NOTE: Emory and Partners call it VUS, (previously reported in patient with optic atrophy, hearing loss, neurogenic bladder, but no diabetes), PMID 28432734)=likely benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.99

ClinPred

0.40

GERP RS

4.9

Varity_R

0.89

gMVP

0.91

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