rs1801208

Variant names:

• chr4-6301162-G-A
• rs1801208
• NM_006005.3:c.1367G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6301162-G-A
• chr4-6301162-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006005.3(WFS1):​c.1367G>A​(p.Arg456His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,612,200 control chromosomes in the GnomAD database, including 2,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R456C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (233 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2185 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 9.34
• Publications: 48 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005521953).
• BP6: Variant 4-6301162-G-A is Benign according to our data. Variant chr4-6301162-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45434.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0897 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.1367G>A	p.Arg456His	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1367G>A	p.Arg456His	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.1367G>A	p.Arg456His	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1367G>A	p.Arg456His	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1460G>A	p.Arg487His	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7773 AN: 152054 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.0967

Gnomad SAS AF: 0.0633

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0537

GnomAD2 exomes AF: 0.0567 AC: 14160 AN: 249686 AF XY: 0.0577

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.0577

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.0911

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0491

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0519 AC: 75746 AN: 1460028 Hom.: 2185 Cov.: 103 AF XY: 0.0522 AC XY: 37887 AN XY: 726372

African (AFR) AF: 0.0393 AC: 1316 AN: 33478

American (AMR) AF: 0.0611 AC: 2731 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 962 AN: 26136

East Asian (EAS) AF: 0.101 AC: 4011 AN: 39694

South Asian (SAS) AF: 0.0637 AC: 5493 AN: 86250

European-Finnish (FIN) AF: 0.0781 AC: 4041 AN: 51716

Middle Eastern (MID) AF: 0.0684 AC: 394 AN: 5764

European-Non Finnish (NFE) AF: 0.0480 AC: 53356 AN: 1111890

Other (OTH) AF: 0.0570 AC: 3442 AN: 60376

GnomAD4 genome AF: 0.0511 AC: 7777 AN: 152172 Hom.: 233 Cov.: 33 AF XY: 0.0526 AC XY: 3916 AN XY: 74394

African (AFR) AF: 0.0367 AC: 1523 AN: 41516

American (AMR) AF: 0.0603 AC: 922 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3472

East Asian (EAS) AF: 0.0967 AC: 500 AN: 5168

South Asian (SAS) AF: 0.0635 AC: 306 AN: 4816

European-Finnish (FIN) AF: 0.0821 AC: 870 AN: 10592

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0493 AC: 3353 AN: 68004

Other (OTH) AF: 0.0546 AC: 115 AN: 2106

Alfa AF: 0.0503 Hom.: 799

Bravo AF: 0.0503

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.0508 AC: 437

ExAC AF: 0.0569 AC: 6912

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.53
Sift	Benign	0.080	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.31
ClinPred		0.053	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.80
Mutation Taster		=96/4	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: rs1801208; hg19: chr4-6302889; COSMIC: COSV56988445; COSMIC: COSV56988445;