rs727503753

Positions:

• chr4-6302118-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_006005.3(WFS1):​c.2323T>G​(p.Phe775Val) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.55

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 Likely_pathogenic. Variant got 9 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, 0.982
• PP5: Variant 4-6302118-T-G is Pathogenic according to our data. Variant chr4-6302118-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166605.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2323T>G	p.Phe775Val	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2323T>G	p.Phe775Val	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2323T>G	p.Phe775Val	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1797A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wolfram syndrome 1 Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs727503753 in Wolfram's syndrome yet. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 05, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe775Val variant in WFS1 has been identified by our laboratory in one Caucasian adolesce nt with low frequency mild to moderate sensorineural hearing loss and segregated with disease in 1 affected relative. It was absent from large population studie s, but present in dbSNP without frequency information (dbSNP rs727503753). Compu tational prediction tools and conservation analysis suggest that the p.Phe775Val variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, while there is some suspicion for a pa thogenic role, the clinical significance of the p.Phe775Val variant is uncertain . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.87		Gain of glycosylation at Y773 (P = 0.0611);Gain of glycosylation at Y773 (P = 0.0611);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.88

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: rs727503753; hg19: chr4-6303845;