rs5018647

Variant names:

• chr4-6291072-A-C
• rs5018647
• NM_006005.3:c.461-125A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-6291072-A-C
• chr4-6291072-A-G
• chr4-6291072-A-T

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.461-125A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,098,338 control chromosomes in the GnomAD database, including 202,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31732 hom., cov: 32)
  • Exomes 𝑓: 0.59 (170871 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0460
• Publications: 16 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-6291072-A-C is Benign according to our data. Variant chr4-6291072-A-C is described in ClinVar as Benign. ClinVar VariationId is 1292285.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.461-125A>C		intron	N/A	NP_005996.2
	WFS1	NM_001145853.1		c.461-125A>C		intron	N/A	NP_001139325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.461-125A>C		intron	N/A	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.461-125A>C		intron	N/A	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.461-125A>C		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97112 AN: 151706 Hom.: 31690 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.594 AC: 562287 AN: 946512 Hom.: 170871 AF XY: 0.599 AC XY: 291542 AN XY: 487092

African (AFR) AF: 0.634 AC: 14787 AN: 23312

American (AMR) AF: 0.734 AC: 26838 AN: 36554

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 14993 AN: 21992

East Asian (EAS) AF: 0.963 AC: 33223 AN: 34490

South Asian (SAS) AF: 0.687 AC: 48366 AN: 70356

European-Finnish (FIN) AF: 0.573 AC: 20323 AN: 35496

Middle Eastern (MID) AF: 0.614 AC: 2943 AN: 4790

European-Non Finnish (NFE) AF: 0.553 AC: 373768 AN: 676134

Other (OTH) AF: 0.623 AC: 27046 AN: 43388

GnomAD4 genome AF: 0.640 AC: 97207 AN: 151826 Hom.: 31732 Cov.: 32 AF XY: 0.643 AC XY: 47688 AN XY: 74168

African (AFR) AF: 0.655 AC: 27136 AN: 41412

American (AMR) AF: 0.702 AC: 10713 AN: 15264

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

East Asian (EAS) AF: 0.941 AC: 4834 AN: 5138

South Asian (SAS) AF: 0.710 AC: 3406 AN: 4794

European-Finnish (FIN) AF: 0.573 AC: 6018 AN: 10508

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

European-Non Finnish (NFE) AF: 0.601 AC: 40809 AN: 67928

Other (OTH) AF: 0.661 AC: 1393 AN: 2108

Alfa AF: 0.532 Hom.: 1985

Bravo AF: 0.651

Asia WGS AF: 0.820 AC: 2851 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.85
CADD	Benign	6.7
DANN	Benign	0.69
PhyloP100		-0.046
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: rs5018647; hg19: chr4-6292799;