4-6291623-T-C

Position:

• chr4-6291623-T-C

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.631+256T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 152,098 control chromosomes in the GnomAD database, including 31,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.64 (31772 hom., cov: 33)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.42

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=-1.01).
• BP6: Variant 4-6291623-T-C is Benign according to our data. Variant chr4-6291623-T-C is described in ClinVar as [Benign]. Clinvar id is 684342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.631+256T>C		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.631+256T>C		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.631+256T>C		intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97271 AN: 151980 Hom.: 31730 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.640 AC: 97365 AN: 152098 Hom.: 31772 Cov.: 33 AF XY: 0.643 AC XY: 47799 AN XY: 74362

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.678

Gnomad4 EAS AF: 0.935

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.601

Gnomad4 OTH AF: 0.661

Alfa AF: 0.623 Hom.: 39142

Bravo AF: 0.651

Asia WGS AF: 0.819 AC: 2848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10012946; hg19: chr4-6293350;