chr4-6302180-G-C

Position:

chr4-6302180-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_006005.3(WFS1):c.2385G>C(p.Glu795Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,612,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E795K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.210

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_006005.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.118661076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2385G>C	p.Glu795Asp	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.2385G>C	p.Glu795Asp	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2385G>C	p.Glu795Asp	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1735C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000692

AC:

AN:

245616

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

133850

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.0000456

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000644

AC:

AN:

1460194

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726382

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000578

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 28432734, 37121227, 21602428, 29529044, Yin2023[Poster]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 795 of the WFS1 protein (p.Glu795Asp). This variant is present in population databases (rs373310972, gnomAD 0.03%). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 21602428, 29529044). ClinVar contains an entry for this variant (Variation ID: 166609). 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 not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 16, 2020

Variant classified as Uncertain Significance - Favor Benign. The p.Glu795Asp variant in WFS1 has been previously reported in one individual with hearing loss, one individual with Wolfram syndrome who also had a second variant in WFS1, and one individual with hearing loss with delayed walking, strabismus and cerebral palsy who also had a second variant in WFS1 (Rohayem 2011, Kobayashi 2018, LMM data). It has also been identified in 0.03% (7/24520) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 166609). Glutamic acid (Glu) at position 795 is not highly conserved in mammals and evolutionary distant species, and several species (Weddell seal, bat, armadillo, 10 fish species) carry an aspartic acid (Asp), supporting that this change at this position may be tolerated, which is consistent with computational prediction tools, which suggest that that this variant may not impact the protein. In summary, while the clinical significance of the p.Glu795Asp variant is uncertain, the lack of evolutionary conservation and computational data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4_strong, PM2_Supporting, PM3_Supporting. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2022

Unlikely to be causative of WFS1-related Wolfram syndrome (AD) or WFS1-related low frequency sensorineural hearing loss (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Type 2 diabetes mellitus;C4551693:Wolfram syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Nov 13, 2022

The c.2385G>C variant has previously been reported in an individual with sporadic hearing loss [PMID: 29529044] and in a compound heterozygous state along with p.(Asp797Val) in individual(s) from a cohort of patients with Wolfram syndrome-related diabetes [PMID:21602428]. This variant has been deposited in ClinVar [ClinVarID: 166609] as a Variant of Uncertain Significance. The c.2385G>C variant is observed in 47 alleles (0.0080% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). The c.2385G>C variant is located in exon 8 of this 8-exon gene and is predicted to replace a moderately conserved glutamic acid with aspartic acid at position 795 in the C-terminal domain of the encoded protein [PMID:29529044]. In silico predictions for p.(Glu795Asp) are inconclusive of the variant's effect [(CADD v1.6 = 21.9, REVEL = 0.522)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.2385G>C p.(Glu795Asp) variant identified in WFS1 is classified as a Variant of Uncertain Significance. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 10, 2015

ACMG Criteria: PP5, BP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.0058

BayesDel_noAF

Uncertain

0.030

CADD

Benign

6.2

DANN

Benign

0.93

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.66

.;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.92

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.33

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.29

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.017

B;B

Vest4

0.20

MutPred

0.18

Gain of glycosylation at S790 (P = 0.0045);Gain of glycosylation at S790 (P = 0.0045);

MVP

0.99

ClinPred

0.015

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.51

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