4-6301521-G-A

Variant names:

• chr4-6301521-G-A
• rs1805069
• NM_006005.3:c.1726G>A
• WFS1 p.Gly576Ser

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.1726G>A​(p.Gly576Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00462 in 1,613,806 control chromosomes in the GnomAD database, including 213 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. G576C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 34)
  • Exomes 𝑓: 0.0040 (188 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:12 O:1
• Conservation: PhyloP100: 5.88
• Publications: 25 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, ClinGen
• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=0.005336702).
• BP6: Variant 4-6301521-G-A is Benign according to our data. Variant chr4-6301521-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45439.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0652 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.1726G>A	p.Gly576Ser	missense	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.1726G>A	p.Gly576Ser	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.1726G>A	p.Gly576Ser	missense	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.1726G>A	p.Gly576Ser	missense	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.1819G>A	p.Gly607Ser	missense	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1672 AN: 152208 Hom.: 25 Cov.: 34

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00954 AC: 2397 AN: 251166 AF XY: 0.00806

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0670

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00396 AC: 5789 AN: 1461478 Hom.: 188 Cov.: 99 AF XY: 0.00374 AC XY: 2721 AN XY: 727078

African (AFR) AF: 0.0235 AC: 788 AN: 33480

American (AMR) AF: 0.0185 AC: 827 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.0877 AC: 3482 AN: 39700

South Asian (SAS) AF: 0.00195 AC: 168 AN: 86254

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53030

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1111994

Other (OTH) AF: 0.00431 AC: 260 AN: 60392

GnomAD4 genome AF: 0.0110 AC: 1674 AN: 152328 Hom.: 25 Cov.: 34 AF XY: 0.0112 AC XY: 837 AN XY: 74486

African (AFR) AF: 0.0244 AC: 1014 AN: 41572

American (AMR) AF: 0.0148 AC: 227 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0712 AC: 368 AN: 5172

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00313 Hom.: 2

Bravo AF: 0.0135

Asia WGS AF: 0.0230 AC: 82 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 6 (1)
-	-	1	Monogenic diabetes (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	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Benign	0.031	D
Sift4G	Uncertain	0.022	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.76
Mutation Taster		=88/12	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1805069;

hg19: chr4-6303248;

COSMIC: COSV56987506;

COSMIC: COSV56987506;