rs114152068

Variant names:

• chr4-6301290-C-A
• NM_006005.3:c.1495C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6301290-C-A
• chr4-6301290-C-G
• chr4-6301290-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_006005.3(WFS1):​c.1495C>A​(p.Leu499Ile) 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 benign outcome for this variant. 12/20 in silico tools predict a benign 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. L499F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

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]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity WFS1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32204318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1495C>A	p.Leu499Ile	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1495C>A	p.Leu499Ile	missense_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1495C>A	p.Leu499Ile	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 102

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 25, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	.;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.87	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T;T
Sift4G	Benign	0.085	T;T
Polyphen		0.10	B;B
Vest4		0.22
MutPred		0.44		Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP		0.82
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.073
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-6303017;