rs2230719

Variant names:

• chr4-6301520-C-T
• rs2230719
• NM_006005.3:c.1725C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-6301520-C-T
• chr4-6301520-C-A
• chr4-6301520-C-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.1725C>T​(p.Ala575Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,824 control chromosomes in the GnomAD database, including 4,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (419 hom., cov: 34)
  • Exomes 𝑓: 0.071 (4025 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.518
• Publications: 14 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-6301520-C-T is Benign according to our data. Variant chr4-6301520-C-T is described in ClinVar as Benign. ClinVar VariationId is 45438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.518 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 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.1725C>T	p.Ala575Ala	synonymous	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1725C>T	p.Ala575Ala	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.1725C>T	p.Ala575Ala	synonymous	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1725C>T	p.Ala575Ala	synonymous	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1818C>T	p.Ala606Ala	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10068 AN: 152206 Hom.: 420 Cov.: 34

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0573 AC: 14395 AN: 251166 AF XY: 0.0585

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0729

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0708 AC: 103422 AN: 1461500 Hom.: 4025 Cov.: 102 AF XY: 0.0705 AC XY: 51292 AN XY: 727098

African (AFR) AF: 0.0741 AC: 2480 AN: 33480

American (AMR) AF: 0.0356 AC: 1591 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0914 AC: 2390 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39698

South Asian (SAS) AF: 0.0617 AC: 5322 AN: 86256

European-Finnish (FIN) AF: 0.0295 AC: 1563 AN: 53044

Middle Eastern (MID) AF: 0.121 AC: 699 AN: 5768

European-Non Finnish (NFE) AF: 0.0767 AC: 85318 AN: 1112004

Other (OTH) AF: 0.0671 AC: 4050 AN: 60390

GnomAD4 genome AF: 0.0661 AC: 10066 AN: 152324 Hom.: 419 Cov.: 34 AF XY: 0.0636 AC XY: 4738 AN XY: 74476

African (AFR) AF: 0.0732 AC: 3042 AN: 41572

American (AMR) AF: 0.0513 AC: 785 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0628 AC: 303 AN: 4826

European-Finnish (FIN) AF: 0.0238 AC: 253 AN: 10622

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0734 AC: 4990 AN: 68024

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0679 Hom.: 584

Bravo AF: 0.0685

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0770

EpiControl AF: 0.0766

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.2
DANN	Benign	0.84
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2230719; hg19: chr4-6303247; COSMIC: COSV56990625; COSMIC: COSV56990625;