chr4-6298186-C-T

Position:

• chr4-6298186-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.862-2471C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 151,882 control chromosomes in the GnomAD database, including 25,105 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 0.57 (25105 hom., cov: 35)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.955

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]

WFS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.862-2471C>T		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.862-2471C>T		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.862-2471C>T		intron_variant		1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86650 AN: 151764 Hom.: 25099 Cov.: 35

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.571 AC: 86683 AN: 151882 Hom.: 25105 Cov.: 35 AF XY: 0.569 AC XY: 42263 AN XY: 74218

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.594

Gnomad4 ASJ AF: 0.647

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.556

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.602

Alfa AF: 0.574 Hom.: 3102

Bravo AF: 0.572

Asia WGS AF: 0.648 AC: 2255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.91

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: rs881796; hg19: chr4-6299913;