rs115346085

chr4-6291218-G-Achr4-6291218-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_006005.3(WFS1):c.482G>A(p.Arg161Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000588 in 1,612,798 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. R161W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.844

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008805037).
• BP6: Variant 4-6291218-G-A is Benign according to our data. Variant chr4-6291218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291218-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.482G>A	p.Arg161Gln	missense_variant	5/8	ENST00000226760.5
WFS1	NM_001145853.1	c.482G>A	p.Arg161Gln	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.482G>A	p.Arg161Gln	missense_variant	5/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000871 AC: 218 AN: 250290 Hom.: 2 AF XY: 0.000709 AC XY: 96 AN XY: 135464

Gnomad AFR exome AF: 0.00709

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1460554 Hom.: 1 Cov.: 35 AF XY: 0.000387 AC XY: 281 AN XY: 726566

Gnomad4 AFR exome AF: 0.00705

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74424

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.00266

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 02, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2013	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	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg161Gln in Exon 05 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.7% (28/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs115346085). -

WFS1-Related Spectrum Disorders 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. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C4551693:Wolfram syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	0.29
Dann	Benign	0.73
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.83	N;N
REVEL	Benign	0.26
Sift	Benign	0.70	T;T
Sift4G	Benign	0.90	T;T
Polyphen		0.0030	B;B
Vest4		0.11
MVP		0.77
ClinPred		0.0017	T
GERP RS		-0.53
Varity_R		0.017
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs115346085; hg19: chr4-6292945; COSMIC: COSV99901474; COSMIC: COSV99901474;