4-6293966-C-G

Position:

• chr4-6293966-C-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.713-1075C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,072 control chromosomes in the GnomAD database, including 31,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.63 (31031 hom., cov: 33)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 1.04

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]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-6293966-C-G is Benign according to our data. Variant chr4-6293966-C-G is described in ClinVar as [Benign]. Clinvar id is 4528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.713-1075C>G		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.713-1075C>G		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.713-1075C>G		intron_variant		1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96092 AN: 151954 Hom.: 30991 Cov.: 33

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.650

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.632 AC: 96182 AN: 152072 Hom.: 31031 Cov.: 33 AF XY: 0.635 AC XY: 47204 AN XY: 74320

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.932

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.566

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.653

Alfa AF: 0.612 Hom.: 3548

Bravo AF: 0.642

Asia WGS AF: 0.812 AC: 2824 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wolfram syndrome 1 Benign:2

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. rs6446482 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 06, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.707, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Diabetes mellitus, noninsulin-dependent, association with Benign:1

Benign, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NG_011700.1(NM_006005.3):c.713-1075C>G (rs6446482) in the WFS1 gene has an allele frequency of 0.647 in African subpopulation in the gnomAD database, including 6277 homozygous. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.70

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: rs6446482; hg19: chr4-6295693;