rs4689391

Positions:

• chr4-6278722-G-A
• chr4-6278722-G-C
• chr4-6278722-G-T

Variant summary

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

The NM_006005.3(WFS1):​c.232+1035G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 152,166 control chromosomes in the GnomAD database, including 26,333 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 0.58 (26333 hom., cov: 34)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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	UniProt
WFS1	NM_006005.3	c.232+1035G>A		intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.232+1035G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.232+1035G>A		intron_variant		1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88097 AN: 152048 Hom.: 26314 Cov.: 34

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.604

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

GnomAD4 genome AF: 0.579 AC: 88148 AN: 152166 Hom.: 26333 Cov.: 34 AF XY: 0.581 AC XY: 43221 AN XY: 74382

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.650

Gnomad4 EAS AF: 0.935

Gnomad4 SAS AF: 0.652

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.606

Alfa AF: 0.582 Hom.: 25621

Bravo AF: 0.586

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.50

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: rs4689391; hg19: chr4-6280449;