NM_006005.3:c.316-120T>C

Variant names:

• chr4-6288867-T-C
• rs4688989
• NM_006005.3:c.316-120T>C

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.316-120T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,455,408 control chromosomes in the GnomAD database, including 291,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33393 hom., cov: 34)
  • Exomes 𝑓: 0.62 (257944 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.73
• Publications: 11 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=-0.95).
• BP6: Variant 4-6288867-T-C is Benign according to our data. Variant chr4-6288867-T-C is described in ClinVar as Benign. ClinVar VariationId is 1292284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 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.316-120T>C		intron	N/A	NP_005996.2
	WFS1	NM_001145853.1		c.316-120T>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.316-120T>C		intron	N/A	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.316-120T>C		intron	N/A	ENSP00000423337.1
	WFS1	ENST00000852027.1		c.316-120T>C		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99615 AN: 152000 Hom.: 33350 Cov.: 34

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.625 AC: 814156 AN: 1303290 Hom.: 257944 Cov.: 19 AF XY: 0.627 AC XY: 405918 AN XY: 647812

African (AFR) AF: 0.715 AC: 21318 AN: 29806

American (AMR) AF: 0.742 AC: 26415 AN: 35594

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 17012 AN: 24506

East Asian (EAS) AF: 0.965 AC: 34066 AN: 35308

South Asian (SAS) AF: 0.700 AC: 53633 AN: 76650

European-Finnish (FIN) AF: 0.577 AC: 27549 AN: 47704

Middle Eastern (MID) AF: 0.639 AC: 2679 AN: 4190

European-Non Finnish (NFE) AF: 0.599 AC: 595648 AN: 994706

Other (OTH) AF: 0.654 AC: 35836 AN: 54826

GnomAD4 genome AF: 0.656 AC: 99717 AN: 152118 Hom.: 33393 Cov.: 34 AF XY: 0.658 AC XY: 48909 AN XY: 74356

African (AFR) AF: 0.707 AC: 29339 AN: 41498

American (AMR) AF: 0.707 AC: 10821 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2364 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4873 AN: 5168

South Asian (SAS) AF: 0.710 AC: 3420 AN: 4818

European-Finnish (FIN) AF: 0.574 AC: 6069 AN: 10570

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40864 AN: 67982

Other (OTH) AF: 0.672 AC: 1418 AN: 2110

Alfa AF: 0.626 Hom.: 3695

Bravo AF: 0.668

Asia WGS AF: 0.825 AC: 2869 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	-0.95
CADD	Benign	0.40
DANN	Benign	0.52
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: rs4688989; hg19: chr4-6290594; COSMIC: COSV56991975; COSMIC: COSV56991975;