rs4689394

Positions:

• chr4-6289276-C-G
• chr4-6289276-C-T

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.460+145C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,118,766 control chromosomes in the GnomAD database, including 227,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32463 hom., cov: 33)
  • Exomes 𝑓: 0.63 (194688 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.897

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=-1.03).
• BP6: Variant 4-6289276-C-G is Benign according to our data. Variant chr4-6289276-C-G is described in ClinVar as [Benign]. Clinvar id is 1230484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.460+145C>G		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.460+145C>G		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.460+145C>G		intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98287 AN: 152040 Hom.: 32431 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.660

GnomAD4 exome AF: 0.628 AC: 607026 AN: 966608 Hom.: 194688 AF XY: 0.630 AC XY: 302699 AN XY: 480380

Gnomad4 AFR exome AF: 0.677

Gnomad4 AMR exome AF: 0.733

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.702

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.601

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.647 AC: 98375 AN: 152158 Hom.: 32463 Cov.: 33 AF XY: 0.648 AC XY: 48216 AN XY: 74380

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.676

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.663

Alfa AF: 0.624 Hom.: 3692

Bravo AF: 0.658

Asia WGS AF: 0.822 AC: 2856 AN: 3476

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 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.59

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: rs4689394; hg19: chr4-6291003;