rs761114952

Variant names:

• chr4-6302311-T-C
• rs761114952
• NM_006005.3:c.2516T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-6302311-T-C
• chr4-6302311-T-A
• chr4-6302311-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_006005.3(WFS1):​c.2516T>C​(p.Val839Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.94
• Publications: 1 publications found

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]

WFS1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant nonsyndromic hearing loss 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 41

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Wolfram syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.34387016).
• BP6: Variant 4-6302311-T-C is Benign according to our data. Variant chr4-6302311-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505203.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.2516T>C	p.Val839Ala	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.2516T>C	p.Val839Ala	missense	Exon 8 of 8	NP_001139325.1	O76024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.2516T>C	p.Val839Ala	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.2516T>C	p.Val839Ala	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.2609T>C	p.Val870Ala	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248476 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458878 Hom.: 0 Cov.: 99 AF XY: 0.00000138 AC XY: 1 AN XY: 725560

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000671 AC: 3 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 35

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.71
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.0074	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.45
Sift	Benign	0.47	T
Sift4G	Benign	0.36	T
Polyphen		0.41	B
Vest4		0.45
MutPred		0.31		Gain of helix (P = 0.0325)
MVP		0.99
ClinPred		0.097	T
GERP RS		4.8
Varity_R		0.093
gMVP		0.83
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs761114952; hg19: chr4-6304038;