4-6301177-C-T

Position:

• chr4-6301177-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2 PM5 BP4_Moderate BP6

The NM_006005.3(WFS1):​c.1382C>T​(p.Thr461Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,904 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T461P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.75

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301176-A-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21069181).
• BP6: Variant 4-6301177-C-T is Benign according to our data. Variant chr4-6301177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229636.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1382C>T	p.Thr461Ile	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1382C>T	p.Thr461Ile	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1382C>T	p.Thr461Ile	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+2738G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459904 Hom.: 0 Cov.: 101 AF XY: 0.00000138 AC XY: 1 AN XY: 726300

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 31, 2015

The p.Thr461Ile variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome or in large population studies. Two diffe rent missense variants in WFS1 at the same amino acid position (p.Thr461Pro and p.Thr461Ser) have been reported in three probands with Wolfram syndrome (Aloi 20 11, Zalloua 2008). Computational prediction tools and conservation analyses sugg est that the p.Thr461Ile variant may not impact the protein, though this informa tion is not predictive enough to rule out pathogenicity. In summary, the clinica l significance of the p.Thr461Ile variant is uncertain. -

Wolfram syndrome 1 Benign:1

Likely benign, 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 rs71530925 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.68
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	.;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.71	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.52	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0060	B;B
Vest4		0.28
MutPred		0.29		Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);
MVP		0.97
ClinPred		0.30	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.77

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: rs71530925; hg19: chr4-6302904;