rs56002719

Variant names:

• chr4-6302122-A-T
• rs56002719
• NM_006005.3:c.2327A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP3 BP4_Strong BP6_Very_Strong BS2

The NM_006005.3(WFS1):​c.2327A>T​(p.Glu776Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,924 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0043 (28 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 8.77
• Publications: 26 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 -13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 23 uncertain in NM_006005.3
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.066612035).
• BP6: Variant 4-6302122-A-T is Benign according to our data. Variant chr4-6302122-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 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.2327A>T	p.Glu776Val	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.2327A>T	p.Glu776Val	missense	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.2327A>T	p.Glu776Val	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.2327A>T	p.Glu776Val	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.2420A>T	p.Glu807Val	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152216 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00380 AC: 941 AN: 247476 AF XY: 0.00377

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00433 AC: 6322 AN: 1460590 Hom.: 28 Cov.: 98 AF XY: 0.00419 AC XY: 3046 AN XY: 726594

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.000716 AC: 32 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86258

European-Finnish (FIN) AF: 0.0110 AC: 573 AN: 52176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00480 AC: 5335 AN: 1111980

Other (OTH) AF: 0.00419 AC: 253 AN: 60380

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152334 Hom.: 3 Cov.: 34 AF XY: 0.00368 AC XY: 274 AN XY: 74488

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00445 AC: 303 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00247

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00409 AC: 496

EpiCase AF: 0.00371

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	WFS1-related disorder (1)
-	-	1	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.067	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MVP		1.0
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.65
gMVP		0.90
Mutation Taster		=89/11	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: rs56002719; hg19: chr4-6303849;