chr4-6302219-C-T

Variant names:

• chr4-6302219-C-T
• rs56035336
• NM_006005.3:c.2424C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_006005.3(WFS1):​c.2424C>T​(p.Ser808Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,610,184 control chromosomes in the GnomAD database, including 2 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 0.00049 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (2 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: -0.692
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 4-6302219-C-T is Benign according to our data. Variant chr4-6302219-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212615.
• BP7: Synonymous conserved (PhyloP=-0.692 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Unknown gene

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.2424C>T	p.Ser808Ser	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.2424C>T	p.Ser808Ser	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.2424C>T	p.Ser808Ser	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.2424C>T	p.Ser808Ser	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.2517C>T	p.Ser839Ser	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000420 AC: 104 AN: 247436 AF XY: 0.000402

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.000587 AC: 856 AN: 1457830 Hom.: 2 Cov.: 98 AF XY: 0.000552 AC XY: 400 AN XY: 724862

African (AFR) AF: 0.000209 AC: 7 AN: 33432

American (AMR) AF: 0.000986 AC: 44 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86094

European-Finnish (FIN) AF: 0.0000580 AC: 3 AN: 51696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000699 AC: 776 AN: 1110266

Other (OTH) AF: 0.000348 AC: 21 AN: 60278

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000403 AC XY: 30 AN XY: 74502

African (AFR) AF: 0.000168 AC: 7 AN: 41586

American (AMR) AF: 0.00111 AC: 17 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000593 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	2	not specified (3)
-	1	-	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	WFS1-related disorder (1)
-	1	-	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.1
DANN	Benign	0.84
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56035336; hg19: chr4-6303946; COSMIC: COSV99901217; COSMIC: COSV99901217;