rs10010131

Variant names:

• chr4-6291188-A-G
• rs10010131
• NM_006005.3:c.461-9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.461-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,444 control chromosomes in the GnomAD database, including 31,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31471 hom., cov: 31)
  • Exomes 𝑓: 0.62 (285946 hom.)
  • Failed GnomAD Quality Control
• Consequence: WFS1 NM_006005.3 intron
• Scores: Splicing: ADA: 0.00005842
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:17
• Conservation: PhyloP100: 0.421
• Publications: 210 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-6291188-A-G is Benign according to our data. Variant chr4-6291188-A-G is described in ClinVar as Benign. ClinVar VariationId is 4527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.461-9A>G		intron	N/A	NP_005996.2
	WFS1	NM_001145853.1		c.461-9A>G		intron	N/A	NP_001139325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.461-9A>G		intron	N/A	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.461-9A>G		intron	N/A	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.461-9A>G		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96669 AN: 151326 Hom.: 31429 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.662 AC: 164492 AN: 248508 AF XY: 0.659

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.931

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.652

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.622 AC: 906540 AN: 1457304 Hom.: 285946 Cov.: 50 AF XY: 0.624 AC XY: 452378 AN XY: 725028

African (AFR) AF: 0.660 AC: 22060 AN: 33418

American (AMR) AF: 0.744 AC: 33228 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 18098 AN: 26120

East Asian (EAS) AF: 0.959 AC: 38045 AN: 39692

South Asian (SAS) AF: 0.702 AC: 60549 AN: 86228

European-Finnish (FIN) AF: 0.575 AC: 29299 AN: 50922

Middle Eastern (MID) AF: 0.628 AC: 3623 AN: 5766

European-Non Finnish (NFE) AF: 0.597 AC: 662684 AN: 1110158

Other (OTH) AF: 0.646 AC: 38954 AN: 60316

GnomAD4 genome AF: 0.639 AC: 96763 AN: 151444 Hom.: 31471 Cov.: 31 AF XY: 0.641 AC XY: 47452 AN XY: 73980

African (AFR) AF: 0.654 AC: 27009 AN: 41278

American (AMR) AF: 0.700 AC: 10670 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2349 AN: 3464

East Asian (EAS) AF: 0.934 AC: 4759 AN: 5096

South Asian (SAS) AF: 0.710 AC: 3407 AN: 4796

European-Finnish (FIN) AF: 0.571 AC: 5982 AN: 10478

Middle Eastern (MID) AF: 0.645 AC: 187 AN: 290

European-Non Finnish (NFE) AF: 0.600 AC: 40662 AN: 67782

Other (OTH) AF: 0.660 AC: 1389 AN: 2106

Alfa AF: 0.625 Hom.: 61871

Bravo AF: 0.651

Asia WGS AF: 0.818 AC: 2846 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.607

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Wolfram syndrome 1 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
1	-	-	Type 2 diabetes mellitus (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.48
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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: rs10010131; hg19: chr4-6292915;