chr4-6302303-G-C

Position:

• chr4-6302303-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_006005.3(WFS1):​c.2508G>C​(p.Lys836Asn) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K836T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.42

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 12 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6302302-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 4-6302303-G-C is Pathogenic according to our data. Variant chr4-6302303-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228313.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-6302303-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2508G>C	p.Lys836Asn	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2508G>C	p.Lys836Asn	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2508G>C	p.Lys836Asn	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1612C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 35

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Wolfram-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 12, 2010

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2016

The p.Lys836Asn variant in WFS1 has been previously reported in a Dutch individu al with hearing loss and optic neuropathy and segregated in two affected family members (Hogewind 2010). This variant has also been identified in an individual with hearing loss by our laboratory and segregated in an affected family member who had hearing loss and vision loss. A missense variant at the same amino acid position (p.Lys836Thr) has been identified in a Japanese individual with low to mid frequency sensorineural hearing loss, and the variant reportedly segregated in 8 affected family members (Fujikawa 2010), suggesting that variants at this p osition are not tolerated. In addition, both of these variants were absent in la rge population studies. Variants in the WFS1 gene have been associated with auto somal dominant low frequency sensorineural hearing loss, autosomal dominant Wolf ram-like syndrome, and autosomal recessive Wolfram syndrome (also known as DIDMO AD). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic based on previous repo rts and segregation with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.062	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.89		Loss of methylation at K836 (P = 0.0143);Loss of methylation at K836 (P = 0.0143);
MVP		1.0
ClinPred		0.86	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.84

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: rs876657675; hg19: chr4-6304030;