rs1046319

Variant names:

• chr4-6302559-C-T
• rs1046319
• NM_006005.3:c.*91C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-6302559-C-T
• chr4-6302559-C-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.*91C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,571,184 control chromosomes in the GnomAD database, including 438,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45624 hom., cov: 35)
  • Exomes 𝑓: 0.74 (392712 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07
• 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: 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=-0.94).
• BP6: Variant 4-6302559-C-T is Benign according to our data. Variant chr4-6302559-C-T is described in ClinVar as Benign. ClinVar VariationId is 349335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 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.*91C>T		3_prime_UTR	Exon 8 of 8	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.*91C>T		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.*91C>T		3_prime_UTR	Exon 8 of 8	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.*91C>T		3_prime_UTR	Exon 8 of 8	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.*91C>T		3_prime_UTR	Exon 9 of 9	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 117147 AN: 152066 Hom.: 45580 Cov.: 35

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.761

GnomAD4 exome AF: 0.741 AC: 1052142 AN: 1419002 Hom.: 392712 Cov.: 28 AF XY: 0.744 AC XY: 523218 AN XY: 703518

African (AFR) AF: 0.839 AC: 27695 AN: 32994

American (AMR) AF: 0.804 AC: 34683 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 20479 AN: 25104

East Asian (EAS) AF: 0.998 AC: 39131 AN: 39206

South Asian (SAS) AF: 0.832 AC: 68789 AN: 82646

European-Finnish (FIN) AF: 0.672 AC: 27097 AN: 40300

Middle Eastern (MID) AF: 0.783 AC: 3731 AN: 4766

European-Non Finnish (NFE) AF: 0.719 AC: 785269 AN: 1091814

Other (OTH) AF: 0.767 AC: 45268 AN: 59030

GnomAD4 genome AF: 0.770 AC: 117249 AN: 152182 Hom.: 45624 Cov.: 35 AF XY: 0.770 AC XY: 57314 AN XY: 74392

African (AFR) AF: 0.838 AC: 34773 AN: 41520

American (AMR) AF: 0.787 AC: 12044 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2824 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5156 AN: 5176

South Asian (SAS) AF: 0.845 AC: 4076 AN: 4824

European-Finnish (FIN) AF: 0.661 AC: 6995 AN: 10584

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 48997 AN: 67990

Other (OTH) AF: 0.764 AC: 1612 AN: 2110

Alfa AF: 0.774 Hom.: 22375

Bravo AF: 0.782

Asia WGS AF: 0.917 AC: 3189 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	-0.94
CADD	Benign	0.41
DANN	Benign	0.52
PhyloP100		-1.1
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: rs1046319; hg19: chr4-6304286;