rs28937890

Positions:

chr4-6301966-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_006005.3(WFS1):c.2171C>T(p.Pro724Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,686 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P724S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 7.43

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 Pathogenic. 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301965-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 4-6301966-C-T is Pathogenic according to our data. Variant chr4-6301966-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4509.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}. Variant chr4-6301966-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2171C>T	p.Pro724Leu	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.2171C>T	p.Pro724Leu	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.2171C>T	p.Pro724Leu	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1949G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248128

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.000315

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460444

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000801

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2018	The WFS1 c.2171C>T; p.Pro724Leu variant (rs28937890) has been previously observed as a homozygote in a pair of siblings from a consanguineous Japanese family with a Wolfram syndrome phenotype (minimally, juvenile-onset diabetes mellitus and optic atrophy; Inoue 1998). Numerous functional studies have demonstrated that this variant effects WFS1 protein stability (Hofmann 2006), localization (Fonseca 2005), increased tendency for aggregation (De Franco 2017), and interactions with ATF6 (Fonseca 2010). This variant is found in the general population with an overall allele frequency of 0.003% (8/243,604 alleles) in the Genome Aggregation Database. Based on the available information, the clinical significance of this variant cannot be determined with certainty. De Franco E et al. Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053. Fonseca SG et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005 Nov 25;280(47):39609-15 Fonseca SG et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010 Mar;120(3):744-55. Hofmann S and Bauer M. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Inoue H et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 04, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been associated with autosomal recessive Wolfram Syndrome (PMID: 9771706, 24890733) and autosomal recessive Optic Atrophy (PMID: 27395765). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abrogates the ability of WFS1 to negatively regulate ATF6-alpha, a transcription factor that is responsible for upregulating stress signaling targets, thereby causing ER-stress mediated apoptosis in pancreatic beta-cells (PMID: 20160352). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	Published functional studies demonstrate a damaging effect resulting in abnormal ERSE reporter activity in pancreatic beta-cells (Fonseca et al., 2005; De Franco et al., 2017); 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: 22983116, 20160352, 11709537, 11317350, 12955714, 24424032, 26435059, 16806192, 21454619, 28468959, 24227685, 27434582, 11244483, 34406036, 34848728, 37185285, 12618560, 24890733, 30245029, 9771706, 33663443, 27395765, 34404380, 36208030, 25211237, 16195229) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16195229, 16806192). 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. ClinVar contains an entry for this variant (Variation ID: 4509). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 9771706, 24890733). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937890, gnomAD 0.03%). This sequence change replaces proline, a(n) neutral and non-polar amino acid, with leucine, a(n) neutral and non-polar amino acid, at codon 724 of the WFS1 protein (p.Pro724Leu). -

Wolfram syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-9.9

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

1.0

ClinPred

0.99

GERP RS

5.5

Varity_R

0.83

gMVP

0.94

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