chr4-6302220-G-A

Position:

• chr4-6302220-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_006005.3(WFS1):​c.2425G>A​(p.Glu809Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.37

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.

• PM1: In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 4-6302220-G-A is Pathogenic according to our data. Variant chr4-6302220-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 215413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302220-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-6302220-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2425G>A	p.Glu809Lys	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2425G>A	p.Glu809Lys	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2425G>A	p.Glu809Lys	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1695C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 98

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolfram-like syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 16, 2021	The WFS1 c.2425G>A (p.Glu809Lys) variant is a missense variant that has been reported in at least six individuals with Wolfram-like syndrome (Matsunaga et al. 2014; Chaussenot et al. 2015; Prochazkova et al. 2016; De Franco et al. 2017). The variant was noted to be found in a de novo state in three individuals for whom parental samples were available for testing (Prochazkova et al. 2016; De Franco et al. 2017). Affected individuals show clinical features of diabetes mellitus, optic atrophy, hearing loss, psychomotor delay, hypotonia and intellectual disability. Dysmorphic features are not common but have been noted in one patient (Prochazkova et al. 2016). The p.Glu809Lys variant is not found in the Genome Aggregation Database in either version 2.1.1 or version 3.1.1 in a region of good sequence coverage, so the variant is presumed to be rare. The Glu809 residue is located in the C-terminal region of the protein. Functional studies have shown that the p.Glu809Lys variant affects protein folding and has a dominant negative effect on the wild-type protein in HeLa and HEK293 cells, as measured by significantly increased endoplasmic reticulum stress response reporter activity in cells expressing the variant protein (De Franco et al. 2017; Batjargal et al. 2020). Based on the available evidence, the p.Glu809Lys variant is classified as pathogenic for Wolfram-like syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 30, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2021

Published functional studies demonstrate that this variant induces endoplasmic reticulum stress by affecting the protein folding and processing (De Franco et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 28468959, 25211237, 27217304) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.94
Sift	Benign	0.042	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.65		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);
MVP		1.0
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.75

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: rs71539673; hg19: chr4-6303947;