chr4-6301847-G-A

Variant names:

• chr4-6301847-G-A
• rs71539668
• NM_006005.3:c.2052G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_006005.3(WFS1):​c.2052G>A​(p.Ala684Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,612,972 control chromosomes in the GnomAD database, including 4 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 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -1.62
• 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):

• 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)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 4-6301847-G-A is Benign according to our data. Variant chr4-6301847-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137917.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2052G>A	p.Ala684Ala	synonymous	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.2052G>A	p.Ala684Ala	synonymous	Exon 8 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.2052G>A	p.Ala684Ala	synonymous	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.2052G>A	p.Ala684Ala	synonymous	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.2145G>A	p.Ala715Ala	synonymous	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152202 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00133 AC: 333 AN: 250228 AF XY: 0.00117

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00150 AC: 2198 AN: 1460652 Hom.: 3 Cov.: 100 AF XY: 0.00143 AC XY: 1042 AN XY: 726672

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.000344 AC: 18 AN: 52296

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00169 AC: 1881 AN: 1111918

Other (OTH) AF: 0.00144 AC: 87 AN: 60374

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152320 Hom.: 1 Cov.: 34 AF XY: 0.00117 AC XY: 87 AN XY: 74476

African (AFR) AF: 0.00111 AC: 46 AN: 41570

American (AMR) AF: 0.00222 AC: 34 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

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: 0.00140 AC: 95 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.00143

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	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	-0.98
CADD	Benign	0.054
DANN	Benign	0.90
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs71539668; hg19: chr4-6303574; COSMIC: COSV56988815; COSMIC: COSV56988815;