chr4-6301627-G-A

Variant names:

• chr4-6301627-G-A
• rs734312
• NM_006005.3:c.1832G>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.1832G>A​(p.Arg611His) variant causes a missense change. The variant allele was found at a frequency of 0.533 in 1,613,864 control chromosomes in the GnomAD database, including 240,154 homozygotes. In-silico tool predicts 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. R611C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (17727 hom., cov: 33)
  • Exomes 𝑓: 0.54 (222427 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.92
• Publications: 121 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 0 benign, 18 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=2.282324E-6).
• BP6: Variant 4-6301627-G-A is Benign according to our data. Variant chr4-6301627-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 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.1832G>A	p.Arg611His	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1832G>A	p.Arg611His	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.1832G>A	p.Arg611His	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1832G>A	p.Arg611His	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1925G>A	p.Arg642His	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65710 AN: 152006 Hom.: 17718 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.552 AC: 138753 AN: 251300 AF XY: 0.557

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.833

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.544 AC: 794851 AN: 1461740 Hom.: 222427 Cov.: 97 AF XY: 0.546 AC XY: 396845 AN XY: 727158

African (AFR) AF: 0.0885 AC: 2963 AN: 33478

American (AMR) AF: 0.641 AC: 28689 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 16738 AN: 26136

East Asian (EAS) AF: 0.846 AC: 33568 AN: 39700

South Asian (SAS) AF: 0.568 AC: 49036 AN: 86258

European-Finnish (FIN) AF: 0.490 AC: 26158 AN: 53338

Middle Eastern (MID) AF: 0.501 AC: 2892 AN: 5768

European-Non Finnish (NFE) AF: 0.542 AC: 602259 AN: 1111952

Other (OTH) AF: 0.539 AC: 32548 AN: 60386

GnomAD4 genome AF: 0.432 AC: 65726 AN: 152124 Hom.: 17727 Cov.: 33 AF XY: 0.436 AC XY: 32442 AN XY: 74346

African (AFR) AF: 0.109 AC: 4528 AN: 41536

American (AMR) AF: 0.561 AC: 8588 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3472

East Asian (EAS) AF: 0.822 AC: 4225 AN: 5138

South Asian (SAS) AF: 0.575 AC: 2766 AN: 4810

European-Finnish (FIN) AF: 0.481 AC: 5094 AN: 10586

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36890 AN: 67964

Other (OTH) AF: 0.473 AC: 1001 AN: 2116

Alfa AF: 0.513 Hom.: 72049

Bravo AF: 0.425

TwinsUK AF: 0.535 AC: 1982

ALSPAC AF: 0.543 AC: 2092

ESP6500AA AF: 0.117 AC: 515

ESP6500EA AF: 0.547 AC: 4703

ExAC AF: 0.536 AC: 65132

Asia WGS AF: 0.645 AC: 2243 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.545

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)
-	-	2	Wolfram syndrome 1 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.49
Sift	Benign	0.085	T
Sift4G	Benign	0.066	T
Polyphen		0.15	B
Vest4		0.13
ClinPred		0.018	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.90
Mutation Taster		=95/5	disease causing (ClinVar)

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: rs734312; hg19: chr4-6303354; COSMIC: COSV56987772; COSMIC: COSV56987772;