rs71539657

Variant names:

• chr4-6301555-G-A
• rs71539657
• NM_006005.3:c.1760G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6301555-G-A
• chr4-6301555-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006005.3(WFS1):​c.1760G>A​(p.Arg587Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R587W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 2.97
• Publications: 11 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024200052).
• BP6: Variant 4-6301555-G-A is Benign according to our data. Variant chr4-6301555-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215361.

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.1760G>A	p.Arg587Gln	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1760G>A	p.Arg587Gln	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.1760G>A	p.Arg587Gln	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1760G>A	p.Arg587Gln	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1853G>A	p.Arg618Gln	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000553 AC: 139 AN: 251378 AF XY: 0.000508

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1461754 Hom.: 0 Cov.: 99 AF XY: 0.000290 AC XY: 211 AN XY: 727188

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00199 AC: 89 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 122 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1112004

Other (OTH) AF: 0.000844 AC: 51 AN: 60394

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.000309 AC XY: 23 AN XY: 74480

African (AFR) AF: 0.000120 AC: 5 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000418 Hom.: 1

Bravo AF: 0.000582

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	2	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Monogenic diabetes (1)
-	1	-	Optic atrophy (1)
-	1	-	Type 2 diabetes mellitus;C4551693:Wolfram syndrome 1 (1)
-	1	-	WFS1-related disorder (1)
-	1	-	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.48	T
Polyphen		0.14	B
Vest4		0.097
MVP		0.92
ClinPred		0.015	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.45
Mutation Taster		=11/89	disease causing

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: rs71539657; hg19: chr4-6303282; COSMIC: COSV56987603; COSMIC: COSV56987603;