4-6291188-A-G

Position:

• chr4-6291188-A-G

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.461-9A>G 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 0.639 in 151,444 control chromosomes in the GnomAD database, including 31,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31471 hom., cov: 31)
  • Exomes 𝑓: 0.62 (285946 hom.)
  • Failed GnomAD Quality Control
• Consequence: WFS1 NM_006005.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005842
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:16
• Conservation: PhyloP100: 0.421

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=-0.88).
• BP6: Variant 4-6291188-A-G is Benign according to our data. Variant chr4-6291188-A-G is described in ClinVar as [Benign]. Clinvar id is 4527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291188-A-G is described in Lovd as [Benign]. Variant chr4-6291188-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.461-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.461-9A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.461-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96669 AN: 151326 Hom.: 31429 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.656

GnomAD3 exomes AF: 0.662 AC: 164492 AN: 248508 Hom.: 55567 AF XY: 0.659 AC XY: 88703 AN XY: 134542

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.931

Gnomad SAS exome AF: 0.706

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.652

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.622 AC: 906540 AN: 1457304 Hom.: 285946 Cov.: 50 AF XY: 0.624 AC XY: 452378 AN XY: 725028

Gnomad4 AFR exome AF: 0.660

Gnomad4 AMR exome AF: 0.744

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.959

Gnomad4 SAS exome AF: 0.702

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.646

GnomAD4 genome AF: 0.639 AC: 96763 AN: 151444 Hom.: 31471 Cov.: 31 AF XY: 0.641 AC XY: 47452 AN XY: 73980

Gnomad4 AFR AF: 0.654

Gnomad4 AMR AF: 0.700

Gnomad4 ASJ AF: 0.678

Gnomad4 EAS AF: 0.934

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.600

Gnomad4 OTH AF: 0.660

Alfa AF: 0.621 Hom.: 34905

Bravo AF: 0.651

Asia WGS AF: 0.818 AC: 2846 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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	Feb 28, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17603484, 19330314, 22958899, 22461567) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wolfram syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	Population allele frequency is 66% (rs10010131; 180,328/274,176 alleles in gnomAD v2.0). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria are met: BA1. -
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. rs10010131 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 06, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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: rs10010131; hg19: chr4-6292915;