chr4-6302558-G-A

Variant names:

• chr4-6302558-G-A
• rs1802453
• NM_006005.3:c.*90G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.*90G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,575,390 control chromosomes in the GnomAD database, including 7,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (576 hom., cov: 36)
  • Exomes 𝑓: 0.094 (6612 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.696
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-6302558-G-A is Benign according to our data. Variant chr4-6302558-G-A is described in ClinVar as Benign. ClinVar VariationId is 349334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.101 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.*90G>A		3_prime_UTR	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.*90G>A		3_prime_UTR	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.*90G>A		3_prime_UTR	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.*90G>A		3_prime_UTR	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.*90G>A		3_prime_UTR	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12623 AN: 152162 Hom.: 576 Cov.: 36

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.0780

GnomAD4 exome AF: 0.0940 AC: 133775 AN: 1423112 Hom.: 6612 Cov.: 32 AF XY: 0.0943 AC XY: 66602 AN XY: 706048

African (AFR) AF: 0.0620 AC: 2048 AN: 33032

American (AMR) AF: 0.0775 AC: 3363 AN: 43388

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2600 AN: 25174

East Asian (EAS) AF: 0.101 AC: 3973 AN: 39250

South Asian (SAS) AF: 0.107 AC: 8890 AN: 82792

European-Finnish (FIN) AF: 0.0748 AC: 3071 AN: 41082

Middle Eastern (MID) AF: 0.132 AC: 639 AN: 4844

European-Non Finnish (NFE) AF: 0.0947 AC: 103582 AN: 1094358

Other (OTH) AF: 0.0948 AC: 5609 AN: 59192

GnomAD4 genome AF: 0.0829 AC: 12625 AN: 152278 Hom.: 576 Cov.: 36 AF XY: 0.0823 AC XY: 6128 AN XY: 74460

African (AFR) AF: 0.0636 AC: 2643 AN: 41564

American (AMR) AF: 0.0832 AC: 1273 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3468

East Asian (EAS) AF: 0.0985 AC: 510 AN: 5176

South Asian (SAS) AF: 0.109 AC: 527 AN: 4826

European-Finnish (FIN) AF: 0.0710 AC: 754 AN: 10614

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0904 AC: 6150 AN: 68016

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0818 Hom.: 69

Bravo AF: 0.0838

Asia WGS AF: 0.101 AC: 349 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.69
DANN	Benign	0.51
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs1802453; hg19: chr4-6304285;