4-6291969-C-G

Variant names:

• chr4-6291969-C-G
• rs1801213
• NM_006005.3:c.684C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006005.3(WFS1):​c.684C>G​(p.Arg228Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,608,700 control chromosomes in the GnomAD database, including 387,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36573 hom., cov: 35)
  • Exomes 𝑓: 0.69 (350762 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0700
• Publications: 33 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):

• Wolfram-like syndrome

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.112).
• BP6: Variant 4-6291969-C-G is Benign according to our data. Variant chr4-6291969-C-G is described in ClinVar as Benign. ClinVar VariationId is 45460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 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.684C>G	p.Arg228Arg	synonymous	Exon 6 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.684C>G	p.Arg228Arg	synonymous	Exon 6 of 8	NP_001139325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.684C>G	p.Arg228Arg	synonymous	Exon 6 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.684C>G	p.Arg228Arg	synonymous	Exon 6 of 8	ENSP00000423337.1
	WFS1	ENST00000683395.1		c.659C>G	p.Ala220Gly	missense	Exon 5 of 7	ENSP00000507124.1

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104906 AN: 152096 Hom.: 36540 Cov.: 35

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.704

GnomAD2 exomes AF: 0.717 AC: 172276 AN: 240328 AF XY: 0.717

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.932

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.691 AC: 1006725 AN: 1456486 Hom.: 350762 Cov.: 71 AF XY: 0.693 AC XY: 501740 AN XY: 723992

African (AFR) AF: 0.671 AC: 22444 AN: 33424

American (AMR) AF: 0.775 AC: 34292 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 20427 AN: 26040

East Asian (EAS) AF: 0.959 AC: 37939 AN: 39562

South Asian (SAS) AF: 0.763 AC: 65011 AN: 85158

European-Finnish (FIN) AF: 0.606 AC: 31561 AN: 52044

Middle Eastern (MID) AF: 0.744 AC: 4248 AN: 5706

European-Non Finnish (NFE) AF: 0.674 AC: 748180 AN: 1110160

Other (OTH) AF: 0.709 AC: 42623 AN: 60150

GnomAD4 genome AF: 0.690 AC: 104991 AN: 152214 Hom.: 36573 Cov.: 35 AF XY: 0.691 AC XY: 51381 AN XY: 74398

African (AFR) AF: 0.671 AC: 27883 AN: 41554

American (AMR) AF: 0.745 AC: 11401 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 2708 AN: 3470

East Asian (EAS) AF: 0.936 AC: 4842 AN: 5174

South Asian (SAS) AF: 0.773 AC: 3732 AN: 4828

European-Finnish (FIN) AF: 0.597 AC: 6326 AN: 10588

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45859 AN: 67972

Other (OTH) AF: 0.707 AC: 1494 AN: 2114

Alfa AF: 0.689 Hom.: 11659

Bravo AF: 0.699

Asia WGS AF: 0.841 AC: 2924 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (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	-0.55
CADD	Benign	6.7
DANN	Benign	0.68
PhyloP100		-0.070
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801213; hg19: chr4-6293696; COSMIC: COSV108089066; COSMIC: COSV108089066;