rs1046320

Variant names:

• chr4-6302617-G-A
• rs1046320
• NM_006005.3:c.*149G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6302617-G-A
• chr4-6302617-G-T

Variant summary

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

The ENST00000226760.5(WFS1):​c.*149G>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 0.595 in 1,162,182 control chromosomes in the GnomAD database, including 209,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24255 hom., cov: 32)
  • Exomes 𝑓: 0.60 (185599 hom.)
• Consequence: WFS1 ENST00000226760.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.728
• Publications: 27 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):

• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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: PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-6302617-G-A is Benign according to our data. Variant chr4-6302617-G-A is described in ClinVar as Benign. ClinVar VariationId is 349337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000226760.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.*149G>A		3_prime_UTR	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.*149G>A		3_prime_UTR	Exon 8 of 8	NP_001139325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.*149G>A		3_prime_UTR	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.*149G>A		3_prime_UTR	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000507765.1	TSL:2	n.3007G>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83255 AN: 151684 Hom.: 24241 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.601 AC: 607682 AN: 1010380 Hom.: 185599 Cov.: 13 AF XY: 0.604 AC XY: 303064 AN XY: 501438

African (AFR) AF: 0.366 AC: 8797 AN: 24044

American (AMR) AF: 0.709 AC: 21247 AN: 29984

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 12982 AN: 19040

East Asian (EAS) AF: 0.932 AC: 31606 AN: 33922

South Asian (SAS) AF: 0.646 AC: 39826 AN: 61654

European-Finnish (FIN) AF: 0.570 AC: 17913 AN: 31410

Middle Eastern (MID) AF: 0.607 AC: 1916 AN: 3156

European-Non Finnish (NFE) AF: 0.585 AC: 446115 AN: 762398

Other (OTH) AF: 0.609 AC: 27280 AN: 44772

GnomAD4 genome AF: 0.549 AC: 83287 AN: 151802 Hom.: 24255 Cov.: 32 AF XY: 0.553 AC XY: 41036 AN XY: 74172

African (AFR) AF: 0.369 AC: 15292 AN: 41436

American (AMR) AF: 0.658 AC: 10044 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2317 AN: 3458

East Asian (EAS) AF: 0.894 AC: 4585 AN: 5126

South Asian (SAS) AF: 0.649 AC: 3123 AN: 4810

European-Finnish (FIN) AF: 0.562 AC: 5933 AN: 10558

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40230 AN: 67834

Other (OTH) AF: 0.582 AC: 1225 AN: 2104

Alfa AF: 0.574 Hom.: 16283

Bravo AF: 0.549

Asia WGS AF: 0.737 AC: 2565 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.77
DANN	Benign	0.52
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1046320; hg19: chr4-6304344;