chr4-6301555-G-A

Position:

chr4-6301555-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006005.3(WFS1):c.1760G>A(p.Arg587Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign 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. R587W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 2.97

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024200052).

BP6

Variant 4-6301555-G-A is Benign according to our data. Variant chr4-6301555-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215361.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1760G>A	p.Arg587Gln	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.1760G>A	p.Arg587Gln	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1760G>A	p.Arg587Gln	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2360C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000553

AC:

139

AN:

251378

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000285

AC:

417

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00467

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.000269

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.000582

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 11, 2017	The p.Arg587Gln variant (rs71539657) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 215361). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.36% (identified in 37 out of 10,152 chromosomes). The arginine at codon 587 is moderately conserved considering 13 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on WFS1 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg587Gln variant cannot be determined with certainty. -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 02, 2017	p.Arg587Gln in exon 8 of WFS1: This variant is not expected to have clinical sig nificance because of its frequency in the general population and the lack of con servation of the amino acid. It has been identified in 0.4% (37/10152) of Ashke nazi Jewish chromosomes Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs71539657). The arginine (Arg) at position 587 is not cons erved across species with 1 mammal (bushbaby) and 10 fish species having a gluta mine (Gln). Additional computational prediction tools do not suggest an impact t o the protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2016	The R587Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports R587Q was observed in 4/8,600 alleles from individuals of European background. The R587Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

WFS1-Related Spectrum Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Type 2 diabetes mellitus;C4551693:Wolfram syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 17, 2022

- -

WFS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The WFS1 c.1760G>A variant is predicted to result in the amino acid substitution p.Arg587Gln. This variant was reported in the homozygous state in an individual with Wolfram syndrome (Li et al. 2018. PubMed ID: 29549887). This variant is reported in 0.36% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 07, 2016

ACMG Criteria: BS2 (type2diabetesgenetics.org), BP4 -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.068

T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.71

.;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.12

Sift

Benign

0.23

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.14

B;B

Vest4

0.097

MVP

0.92

ClinPred

0.015

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.45

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