rs5018648

Variant names:

• chr4-6291091-C-G
• rs5018648
• NM_006005.3:c.461-106C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-6291091-C-G
• chr4-6291091-C-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.461-106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,293,360 control chromosomes in the GnomAD database, including 241,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31749 hom., cov: 31)
  • Exomes 𝑓: 0.60 (209303 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70
• Publications: 15 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-6291091-C-G is Benign according to our data. Variant chr4-6291091-C-G is described in ClinVar as Benign. ClinVar VariationId is 1231545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 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.461-106C>G		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.461-106C>G		intron	N/A	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.461-106C>G		intron	N/A	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.461-106C>G		intron	N/A	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.461-106C>G		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97165 AN: 151776 Hom.: 31707 Cov.: 31

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.600 AC: 684561 AN: 1141464 Hom.: 209303 AF XY: 0.604 AC XY: 350246 AN XY: 579754

African (AFR) AF: 0.641 AC: 17369 AN: 27112

American (AMR) AF: 0.735 AC: 29343 AN: 39896

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 16196 AN: 23672

East Asian (EAS) AF: 0.963 AC: 35416 AN: 36784

South Asian (SAS) AF: 0.692 AC: 52973 AN: 76592

European-Finnish (FIN) AF: 0.570 AC: 21737 AN: 38134

Middle Eastern (MID) AF: 0.619 AC: 3212 AN: 5188

European-Non Finnish (NFE) AF: 0.565 AC: 476994 AN: 844266

Other (OTH) AF: 0.629 AC: 31321 AN: 49820

GnomAD4 genome AF: 0.640 AC: 97260 AN: 151896 Hom.: 31749 Cov.: 31 AF XY: 0.643 AC XY: 47747 AN XY: 74252

African (AFR) AF: 0.655 AC: 27135 AN: 41408

American (AMR) AF: 0.702 AC: 10713 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2355 AN: 3472

East Asian (EAS) AF: 0.941 AC: 4854 AN: 5158

South Asian (SAS) AF: 0.711 AC: 3420 AN: 4812

European-Finnish (FIN) AF: 0.572 AC: 6029 AN: 10538

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40817 AN: 67928

Other (OTH) AF: 0.661 AC: 1394 AN: 2110

Alfa AF: 0.488 Hom.: 1266

Bravo AF: 0.651

Asia WGS AF: 0.820 AC: 2852 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0030
DANN	Benign	0.48
PhyloP100		-2.7
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: rs5018648; hg19: chr4-6292818;