4-6300792-G-A

Variant names:

• chr4-6300792-G-A
• rs1801212
• NM_006005.3:c.997G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.997G>A​(p.Val333Ile) variant causes a missense change. The variant allele was found at a frequency of 0.749 in 1,613,806 control chromosomes in the GnomAD database, including 457,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V333L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.80 (50072 hom., cov: 30)
  • Exomes 𝑓: 0.74 (407883 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.07
• Publications: 93 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 19 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=1.7407621E-6).
• BP6: Variant 4-6300792-G-A is Benign according to our data. Variant chr4-6300792-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.997G>A	p.Val333Ile	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.997G>A	p.Val333Ile	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.997G>A	p.Val333Ile	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.997G>A	p.Val333Ile	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1090G>A	p.Val364Ile	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122007 AN: 151814 Hom.: 50011 Cov.: 30

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.781 AC: 196436 AN: 251462 AF XY: 0.778

Gnomad AFR exome AF: 0.955

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.814

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.744 AC: 1087224 AN: 1461872 Hom.: 407883 Cov.: 99 AF XY: 0.746 AC XY: 542183 AN XY: 727236

African (AFR) AF: 0.961 AC: 32161 AN: 33480

American (AMR) AF: 0.808 AC: 36135 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.812 AC: 21226 AN: 26136

East Asian (EAS) AF: 0.998 AC: 39626 AN: 39700

South Asian (SAS) AF: 0.834 AC: 71902 AN: 86258

European-Finnish (FIN) AF: 0.665 AC: 35519 AN: 53418

Middle Eastern (MID) AF: 0.796 AC: 4590 AN: 5768

European-Non Finnish (NFE) AF: 0.719 AC: 799262 AN: 1111998

Other (OTH) AF: 0.775 AC: 46803 AN: 60394

GnomAD4 genome AF: 0.804 AC: 122131 AN: 151934 Hom.: 50072 Cov.: 30 AF XY: 0.803 AC XY: 59635 AN XY: 74242

African (AFR) AF: 0.952 AC: 39496 AN: 41470

American (AMR) AF: 0.801 AC: 12235 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2809 AN: 3468

East Asian (EAS) AF: 0.996 AC: 5131 AN: 5150

South Asian (SAS) AF: 0.847 AC: 4060 AN: 4792

European-Finnish (FIN) AF: 0.661 AC: 6975 AN: 10548

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 48978 AN: 67924

Other (OTH) AF: 0.791 AC: 1668 AN: 2110

Alfa AF: 0.755 Hom.: 168587

Bravo AF: 0.820

TwinsUK AF: 0.714 AC: 2649

ALSPAC AF: 0.716 AC: 2759

ESP6500AA AF: 0.947 AC: 4172

ESP6500EA AF: 0.724 AC: 6224

ExAC AF: 0.782 AC: 94911

Asia WGS AF: 0.929 AC: 3229 AN: 3476

EpiCase AF: 0.725

EpiControl AF: 0.732

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 (1)
-	-	1	WFS1-Related Spectrum Disorders (1)
-	-	1	Wolfram syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.56
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.8	N
PhyloP100		4.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.070
ClinPred		0.0027	T
GERP RS		3.4
Varity_R		0.036
gMVP		0.66
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1801212; hg19: chr4-6302519; COSMIC: COSV105845938;