4-6301470-G-A

Position:

chr4-6301470-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1PM5BP4_StrongBP6_Very_StrongBS2

The ENST00000226760.5(WFS1):c.1675G>A(p.Ala559Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00485 in 1,612,772 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A559V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0050 ( 20 hom. )

Consequence

WFS1
ENST00000226760.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 5.49

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 Benign. Variant got -12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in ENST00000226760.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301471-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2734643.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.010330886).

BP6

Variant 4-6301470-G-A is Benign according to our data. Variant chr4-6301470-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301470-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1675G>A	p.Ala559Thr	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.1675G>A	p.Ala559Thr	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.1675G>A	p.Ala559Thr	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2445C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

509

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00561

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00396

AC:

992

AN:

250512

Hom.:

AF XY:

0.00399

AC XY:

541

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00385

Gnomad FIN exome

AF:

0.00574

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00501

AC:

7318

AN:

1460404

Hom.:

Cov.:

100

AF XY:

0.00496

AC XY:

3604

AN XY:

726634

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00371

Gnomad4 FIN exome

AF:

0.00591

Gnomad4 NFE exome

AF:

0.00570

Gnomad4 OTH exome

AF:

0.00397

GnomAD4 genome

AF:

0.00335

AC:

511

AN:

152368

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00561

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00453

Hom.:

Bravo

AF:

0.00303

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00451

AC:

548

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:9

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 27, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WFS1: PM5, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2016	p.Ala559Thr in Exon 08 of WFS1: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (416/66596) European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; r s55814513). -

WFS1-Related Spectrum Disorders

Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 11, 2019

ACMG criteria: BS2 (71 cases and 81 controls in type2diabetesgenetics.org) + BS1 (0.6 MAF in gnomAD European and ENF) = benign (REVEL 0.407 + PP3/3 predictors + BP4/6 predictors = conflicting evidence, not using) -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Wolfram syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs55814513 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.00053

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

.;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.96

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.37

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.43

B;B

Vest4

0.16

MVP

0.95

ClinPred

0.0083

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.69

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