rs1046317

Variant names:

• chr4-6302515-T-C
• rs1046317
• NM_006005.3:c.*47T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-6302515-T-C
• chr4-6302515-T-A
• chr4-6302515-T-G

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.*47T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 1,607,056 control chromosomes in the GnomAD database, including 396,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40075 hom., cov: 35)
  • Exomes 𝑓: 0.70 (356494 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.380
• Publications: 37 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=-0.98).
• BP6: Variant 4-6302515-T-C is Benign according to our data. Variant chr4-6302515-T-C is described in ClinVar as Benign. ClinVar VariationId is 349332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 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.*47T>C		3_prime_UTR	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.*47T>C		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.*47T>C		3_prime_UTR	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.*47T>C		3_prime_UTR	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.*47T>C		3_prime_UTR	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109746 AN: 152114 Hom.: 40018 Cov.: 35

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.941

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.728

GnomAD2 exomes AF: 0.728 AC: 176768 AN: 242812 AF XY: 0.725

Gnomad AFR exome AF: 0.781

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.788

Gnomad EAS exome AF: 0.941

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.722

GnomAD4 exome AF: 0.697 AC: 1014400 AN: 1454824 Hom.: 356494 Cov.: 49 AF XY: 0.698 AC XY: 505387 AN XY: 723546

African (AFR) AF: 0.782 AC: 26135 AN: 33442

American (AMR) AF: 0.785 AC: 34998 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20564 AN: 26110

East Asian (EAS) AF: 0.962 AC: 38150 AN: 39646

South Asian (SAS) AF: 0.756 AC: 65064 AN: 86112

European-Finnish (FIN) AF: 0.606 AC: 29442 AN: 48576

Middle Eastern (MID) AF: 0.755 AC: 4238 AN: 5614

European-Non Finnish (NFE) AF: 0.678 AC: 752405 AN: 1110444

Other (OTH) AF: 0.720 AC: 43404 AN: 60270

GnomAD4 genome AF: 0.722 AC: 109862 AN: 152232 Hom.: 40075 Cov.: 35 AF XY: 0.720 AC XY: 53570 AN XY: 74420

African (AFR) AF: 0.778 AC: 32353 AN: 41562

American (AMR) AF: 0.759 AC: 11612 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2726 AN: 3472

East Asian (EAS) AF: 0.942 AC: 4863 AN: 5164

South Asian (SAS) AF: 0.764 AC: 3687 AN: 4824

European-Finnish (FIN) AF: 0.592 AC: 6269 AN: 10592

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 46059 AN: 67998

Other (OTH) AF: 0.731 AC: 1542 AN: 2110

Alfa AF: 0.703 Hom.: 100504

Bravo AF: 0.737

Asia WGS AF: 0.849 AC: 2953 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	not specified (1)
-	-	1	WFS1-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.1
DANN	Benign	0.42
PhyloP100		-0.38
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: rs1046317; hg19: chr4-6304242; COSMIC: COSV56988128; COSMIC: COSV56988128;