rs797045076

chr4-6302440-TTTTC-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006005.3(WFS1):c.2648_2651del(p.Phe883SerfsTer68) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: WFS1 NM_006005.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.36

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-6302440-TTTTC-T is Pathogenic according to our data. Variant chr4-6302440-TTTTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302440-TTTTC-T is described in Lovd as [Likely_pathogenic]. Variant chr4-6302440-TTTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2648_2651del	p.Phe883SerfsTer68	frameshift_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2648_2651del	p.Phe883SerfsTer68	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2648_2651del	p.Phe883SerfsTer68	frameshift_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1471_1337+1474del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152246 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000920 AC: 23 AN: 250026 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000227 AC: 331 AN: 1460828 Hom.: 0 AF XY: 0.000213 AC XY: 155 AN XY: 726734

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152246 Hom.: 0 Cov.: 35 AF XY: 0.000134 AC XY: 10 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11260218, 26633545, 10521293, 16151413, 26875006, 30507261, 33841295, 23748048) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change results in a frameshift in the WFS1 gene (p.Phe883Serfs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the WFS1 protein and extend the protein by 59 additional amino acid residues. This variant is present in population databases (rs772120569, gnomAD 0.02%). This frameshift has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 10521293, 11260218, 16151413, 28432734). This variant is also known as 2646-2649del. ClinVar contains an entry for this variant (Variation ID: 209207). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -

Wolfram syndrome 1 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 04, 2015	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant [C755R] in a 38-year-old female with Asperger, ataxia, optic atrophy, progressive vision impairment, spastic bladder, chronic fatigue, irregular menses. Variant is pathogenic in recessive state. Found once in our laboratory heterozygous in a 48-year-old male with type 2 diabetes and family history of sudden death. -
Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs797045076 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 08, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong, PP1 strong -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs797045076; hg19: chr4-6304167;