NM_006005.3:c.-6+32_-6+49dupGTGGCTGTGGGCAGCGCG

Variant names:

• chr4-6270040-G-GGCGCGGTGGCTGTGGGCA
• rs71528898
• NM_006005.3:c.-6+32_-6+49dupGTGGCTGTGGGCAGCGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006005.3(WFS1):​c.-6+32_-6+49dupGTGGCTGTGGGCAGCGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,020 control chromosomes in the GnomAD database, including 4,631 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (4630 hom., cov: 29)
  • Exomes 𝑓: 0.081 (1 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 4-6270040-G-GGCGCGGTGGCTGTGGGCA is Benign according to our data. Variant chr4-6270040-G-GGCGCGGTGGCTGTGGGCA is described in ClinVar as [Benign]. Clinvar id is 1233567.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.-6+32_-6+49dupGTGGCTGTGGGCAGCGCG		intron_variant	Intron 1 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.-2+32_-2+49dupGTGGCTGTGGGCAGCGCG		intron_variant	Intron 1 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.-6+32_-6+49dupGTGGCTGTGGGCAGCGCG		intron_variant	Intron 1 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32117 AN: 151824 Hom.: 4612 Cov.: 29

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.0814 AC: 7 AN: 86 Hom.: 1 Cov.: 0 AF XY: 0.106 AC XY: 7 AN XY: 66

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0658 AC: 5 AN: 76

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.212 AC: 32172 AN: 151934 Hom.: 4630 Cov.: 29 AF XY: 0.208 AC XY: 15482 AN XY: 74260

African (AFR) AF: 0.406 AC: 16782 AN: 41352

American (AMR) AF: 0.157 AC: 2397 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 526 AN: 3466

East Asian (EAS) AF: 0.0627 AC: 324 AN: 5166

South Asian (SAS) AF: 0.183 AC: 881 AN: 4826

European-Finnish (FIN) AF: 0.115 AC: 1218 AN: 10572

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9409 AN: 67954

Other (OTH) AF: 0.185 AC: 392 AN: 2116

Alfa AF: 0.166 Hom.: 247

Asia WGS AF: 0.156 AC: 542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71528898; hg19: chr4-6271767;