rs1553876694

Positions:

• chr4-6289107-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_006005.3(WFS1):​c.436C>T​(p.Arg146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,762 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.22

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]

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, 0.766
• PP5: Variant 4-6289107-C-T is Pathogenic according to our data. Variant chr4-6289107-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517251.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	UniProt
WFS1	NM_006005.3	c.436C>T	p.Arg146Cys	missense_variant	4/8	ENST00000226760.5
WFS1	NM_001145853.1	c.436C>T	p.Arg146Cys	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.436C>T	p.Arg146Cys	missense_variant	4/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1428762 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707582

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 rs1553876694 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

Feb 16, 2017

The p.Arg146Cys variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome. Data from large population studies are in sufficient to assess the frequency of this variant. Computational prediction too ls and conservation analysis suggest that the p.Arg146Cys variant may impact the protein, though this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the p.Arg146Cys variant is uncer tain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.38		Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);
MVP		1.0
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.46
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553876694; hg19: chr4-6290834; COSMIC: COSV56987947; COSMIC: COSV56987947;