4-6301295-C-T

Variant names:

• chr4-6301295-C-T
• rs1801214
• NM_006005.3:c.1500C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_006005.3(WFS1):​c.1500C>T​(p.Asn500Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,610,910 control chromosomes in the GnomAD database, including 319,197 homozygotes. 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: 𝑓 0.64 (32210 hom., cov: 33)
  • Exomes 𝑓: 0.62 (286987 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.211
• Publications: 133 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-6301295-C-T is Benign according to our data. Variant chr4-6301295-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45437.
• BP7: Synonymous conserved (PhyloP=-0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

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.1500C>T	p.Asn500Asn	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1500C>T	p.Asn500Asn	synonymous	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.1500C>T	p.Asn500Asn	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1500C>T	p.Asn500Asn	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000673642.1		c.1159C>T	p.Arg387Cys	missense	Exon 7 of 7	ENSP00000501242.1	A0A669KBF0

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97912 AN: 152012 Hom.: 32162 Cov.: 33

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.665 AC: 165988 AN: 249436 AF XY: 0.662

Gnomad AFR exome AF: 0.673

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.940

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.623 AC: 909064 AN: 1458780 Hom.: 286987 Cov.: 94 AF XY: 0.625 AC XY: 453566 AN XY: 725876

African (AFR) AF: 0.676 AC: 22620 AN: 33478

American (AMR) AF: 0.745 AC: 33311 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 18188 AN: 26134

East Asian (EAS) AF: 0.962 AC: 38192 AN: 39698

South Asian (SAS) AF: 0.695 AC: 59961 AN: 86258

European-Finnish (FIN) AF: 0.573 AC: 28860 AN: 50376

Middle Eastern (MID) AF: 0.628 AC: 3623 AN: 5768

European-Non Finnish (NFE) AF: 0.598 AC: 665173 AN: 1111978

Other (OTH) AF: 0.648 AC: 39136 AN: 60370

GnomAD4 genome AF: 0.644 AC: 98017 AN: 152130 Hom.: 32210 Cov.: 33 AF XY: 0.646 AC XY: 48027 AN XY: 74362

African (AFR) AF: 0.670 AC: 27831 AN: 41512

American (AMR) AF: 0.701 AC: 10724 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2367 AN: 3472

East Asian (EAS) AF: 0.940 AC: 4855 AN: 5164

South Asian (SAS) AF: 0.703 AC: 3387 AN: 4818

European-Finnish (FIN) AF: 0.567 AC: 5997 AN: 10578

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40915 AN: 67978

Other (OTH) AF: 0.660 AC: 1393 AN: 2112

Alfa AF: 0.626 Hom.: 69648

Bravo AF: 0.656

Asia WGS AF: 0.818 AC: 2844 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.612

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	1	-	Type 2 diabetes mellitus (1)
-	-	1	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.31
DANN	Benign	0.43
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs1801214; hg19: chr4-6303022; COSMIC: COSV108089067; COSMIC: COSV108089067;