rs35031397

chr4-6301089-C-Gchr4-6301089-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_006005.3(WFS1):c.1294C>G(p.Leu432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,054 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts 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. L432Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (20 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 1.74

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_006005.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301090-T-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.03004542).
• BP6: Variant 4-6301089-C-G is Benign according to our data. Variant chr4-6301089-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137913.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1, Likely_benign=4}. Variant chr4-6301089-C-G is described in Lovd as [Benign]. Variant chr4-6301089-C-G 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.1294C>G	p.Leu432Val	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1294C>G	p.Leu432Val	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1294C>G	p.Leu432Val	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2826G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00390 AC: 981 AN: 251294 Hom.: 2 AF XY: 0.00405 AC XY: 550 AN XY: 135826

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00439

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00381 AC: 5566 AN: 1461746 Hom.: 20 Cov.: 103 AF XY: 0.00381 AC XY: 2771 AN XY: 727182

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.000357

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00503

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74472

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00498 Hom.: 2

Bravo AF: 0.00351

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00362 AC: 439

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00628

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2014	Leu432Val in exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.5% (43/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35031397). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -

not provided Benign:5

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	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	WFS1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 22, 2016

ACMG Criteria:PP3, BP6 (ClinVar with 2 submitters calling this variant benign/Partners and GeneDx) Notes: no statistical difference between [deafness and DM] and 49 controls with this variant in Domenech et al 2002 EJHG (PMID:12107816). -

WFS1-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Wolfram syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.030	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.78
MVP		0.95
ClinPred		0.040	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.81

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

Other links and lift over

dbSNP: rs35031397; hg19: chr4-6302816;