rs4689397

Positions:

• chr4-6297660-G-A
• chr4-6297660-G-C

Variant summary

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

The NM_006005.3(WFS1):​c.861+2471G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 151,922 control chromosomes in the GnomAD database, including 26,286 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 (26286 hom., cov: 31)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.861+2471G>A		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.861+2471G>A		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.861+2471G>A		intron_variant		1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1338-5001C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87695 AN: 151804 Hom.: 26271 Cov.: 31

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.611

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

GnomAD4 genome AF: 0.578 AC: 87737 AN: 151922 Hom.: 26286 Cov.: 31 AF XY: 0.580 AC XY: 43055 AN XY: 74220

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.666

Gnomad4 ASJ AF: 0.660

Gnomad4 EAS AF: 0.934

Gnomad4 SAS AF: 0.643

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.613

Alfa AF: 0.448 Hom.: 1201

Bravo AF: 0.581

Asia WGS AF: 0.753 AC: 2620 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.13
DANN	Benign	0.52

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: rs4689397; hg19: chr4-6299387;