rs104893882

Positions:

• chr4-6301696-A-C
• chr4-6301696-A-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.1901A>C​(p.Lys634Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,738 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K634Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.00

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 4-6301696-A-C is Pathogenic according to our data. Variant chr4-6301696-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 4524.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-6301696-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.1901A>C	p.Lys634Thr	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1901A>C	p.Lys634Thr	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1901A>C	p.Lys634Thr	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2219T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461738 Hom.: 0 Cov.: 98 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.87
Sift	Benign	0.099	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.84		Loss of methylation at K634 (P = 0.007);Loss of methylation at K634 (P = 0.007);
MVP		1.0
ClinPred		0.91	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.91

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: rs104893882; hg19: chr4-6303423;