rs747678800

chr4-6301347-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006005.3(WFS1):c.1552A>G(p.Met518Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000295 in 1,460,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M518I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.1552A>G	p.Met518Val	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1552A>G	p.Met518Val	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1552A>G	p.Met518Val	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2568T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250510 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135518

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1460006 Hom.: 0 Cov.: 99 AF XY: 0.0000303 AC XY: 22 AN XY: 726402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000939 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2015

The p.Met518Val variant in WFS1 has been reported in 1 Japanese individual with some of the clinical features of Wolfram Syndrome, who also carries a second var iant (p.Leu432Val) in WFS1 (Matsunaga 2014). The p.Met518Val variant has also be en identified in 2/66566 of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org); though this frequency is not high e nough to rule out a pathogenic role. However, it should be noted that another va riant at this amino acid residue (p.Met518Ile) has been identified in 0.6% (63/1 0382) of African American chromosomes by the Exome Aggregation Consortium, sugge sting that variation at this position may be tolerated (ExAC, http://exac.broadi nstitute.org; dbSNP rs138232538). In addition, the p.Leu432Val variant identifie d in the affected individual in Matasunaga et al. (2014) has been also identifie d in 358/66730 (0.5%) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs35031397) suggesting that this variant is benign and, therefore, making it unlikely that these variants are rel ated to the features seen in that individual. Computational prediction tools and conservation analysis of the p.Met518Val variant do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f the p.Met518Val variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2020

Previously reported as heterozygous in an individual with diabetes mellitus, optic atrophy, and brain atrophy who was also heterozygous for a second variant in WFS1 (Matsunaga et al., 2014); Not observed at a 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: 25211237) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Pathogenic	0.92
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.78	P;P
Vest4		0.91
MutPred		0.73		Gain of methylation at R517 (P = 0.1619);Gain of methylation at R517 (P = 0.1619);
MVP		0.87
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.34
gMVP		0.87

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: rs747678800; hg19: chr4-6303074;