rs9998519

Positions:

• chr4-6291182-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.461-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 151,502 control chromosomes in the GnomAD database, including 30,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30608 hom., cov: 31)
  • Exomes 𝑓: 0.62 (284228 hom.)
  • Failed GnomAD Quality Control
• Consequence: WFS1 NM_006005.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.409

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-6291182-C-T is Benign according to our data. Variant chr4-6291182-C-T is described in ClinVar as [Benign]. Clinvar id is 45459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291182-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.461-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.461-15C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.461-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95323 AN: 151384 Hom.: 30570 Cov.: 31

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.648

GnomAD3 exomes AF: 0.658 AC: 163193 AN: 248086 Hom.: 54739 AF XY: 0.656 AC XY: 88080 AN XY: 134344

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.919

Gnomad SAS exome AF: 0.705

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.593

Gnomad OTH exome AF: 0.649

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.620 AC: 903560 AN: 1456244 Hom.: 284228 Cov.: 48 AF XY: 0.622 AC XY: 450961 AN XY: 724520

Gnomad4 AFR exome AF: 0.629

Gnomad4 AMR exome AF: 0.742

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.949

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.643

GnomAD4 genome AF: 0.630 AC: 95409 AN: 151502 Hom.: 30608 Cov.: 31 AF XY: 0.632 AC XY: 46777 AN XY: 74012

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.695

Gnomad4 ASJ AF: 0.675

Gnomad4 EAS AF: 0.924

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.570

Gnomad4 NFE AF: 0.599

Gnomad4 OTH AF: 0.652

Alfa AF: 0.622 Hom.: 5959

Bravo AF: 0.640

Asia WGS AF: 0.811 AC: 2822 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	461-15C>T in Intron 04 of WFS1: This variant is not expected to have clinical si gnificance because it has been identified in 38.9% (2732/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs9998519). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

WFS1-Related Spectrum Disorders 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 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. -

Wolfram syndrome 1 Benign:1

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. rs9998519 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.38

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: rs9998519; hg19: chr4-6292909;