4-6298213-C-T

Position:

• chr4-6298213-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006005.3(WFS1):​c.862-2444C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 152,146 control chromosomes in the GnomAD database, including 20,616 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (20616 hom., cov: 35)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.76

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.862-2444C>T		intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.862-2444C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.862-2444C>T		intron_variant		1	NM_006005.3	P2
	ENST00000661896.1	n.1338-5554G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77278 AN: 152028 Hom.: 20602 Cov.: 35

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.542

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

GnomAD4 genome AF: 0.508 AC: 77306 AN: 152146 Hom.: 20616 Cov.: 35 AF XY: 0.509 AC XY: 37868 AN XY: 74380

Gnomad4 AFR AF: 0.372

Gnomad4 AMR AF: 0.593

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.825

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.543

Alfa AF: 0.544 Hom.: 27517

Bravo AF: 0.510

Asia WGS AF: 0.656 AC: 2284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.63

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: rs3821943; hg19: chr4-6299940;