rs9998519

Variant names:

• chr4-6291182-C-T
• rs9998519
• NM_006005.3:c.461-15C>T

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.461-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 151,502 control chromosomes in the GnomAD database, including 30,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30608 hom., cov: 31)
  • Exomes 𝑓: 0.62 (284228 hom.)
  • Failed GnomAD Quality Control
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.409
• Publications: 21 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-6291182-C-T is Benign according to our data. Variant chr4-6291182-C-T is described in ClinVar as Benign. ClinVar VariationId is 45459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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.461-15C>T		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.461-15C>T		intron	N/A	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.461-15C>T		intron	N/A	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.461-15C>T		intron	N/A	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.461-15C>T		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95323 AN: 151384 Hom.: 30570 Cov.: 31

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.658 AC: 163193 AN: 248086 AF XY: 0.656

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.919

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.593

Gnomad OTH exome AF: 0.649

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.620 AC: 903560 AN: 1456244 Hom.: 284228 Cov.: 48 AF XY: 0.622 AC XY: 450961 AN XY: 724520

African (AFR) AF: 0.629 AC: 21031 AN: 33418

American (AMR) AF: 0.742 AC: 33141 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 18024 AN: 26110

East Asian (EAS) AF: 0.949 AC: 37681 AN: 39690

South Asian (SAS) AF: 0.701 AC: 60438 AN: 86204

European-Finnish (FIN) AF: 0.575 AC: 29108 AN: 50666

Middle Eastern (MID) AF: 0.625 AC: 3604 AN: 5762

European-Non Finnish (NFE) AF: 0.597 AC: 661775 AN: 1109430

Other (OTH) AF: 0.643 AC: 38758 AN: 60288

GnomAD4 genome AF: 0.630 AC: 95409 AN: 151502 Hom.: 30608 Cov.: 31 AF XY: 0.632 AC XY: 46777 AN XY: 74012

African (AFR) AF: 0.626 AC: 25847 AN: 41288

American (AMR) AF: 0.695 AC: 10597 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2337 AN: 3462

East Asian (EAS) AF: 0.924 AC: 4697 AN: 5086

South Asian (SAS) AF: 0.709 AC: 3416 AN: 4816

European-Finnish (FIN) AF: 0.570 AC: 5985 AN: 10504

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

European-Non Finnish (NFE) AF: 0.599 AC: 40620 AN: 67800

Other (OTH) AF: 0.652 AC: 1373 AN: 2106

Alfa AF: 0.623 Hom.: 6114

Bravo AF: 0.640

Asia WGS AF: 0.811 AC: 2822 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.82
CADD	Benign	2.3
DANN	Benign	0.38
PhyloP100		0.41
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: rs9998519; hg19: chr4-6292909;