chr4-6295290-G-A

Variant names:

• chr4-6295290-G-A
• rs7691824
• NM_006005.3:c.861+101G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006005.3(WFS1):​c.861+101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,449,676 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (87 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (162 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.464
• 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)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-6295290-G-A is Benign according to our data. Variant chr4-6295290-G-A is described in ClinVar as [Benign]. Clinvar id is 1295949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.861+101G>A		intron_variant	Intron 7 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.861+101G>A		intron_variant	Intron 7 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.861+101G>A		intron_variant	Intron 7 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2622 AN: 152168 Hom.: 86 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00637

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00439 AC: 5699 AN: 1297390 Hom.: 162 AF XY: 0.00524 AC XY: 3413 AN XY: 651020

African (AFR) AF: 0.0574 AC: 1752 AN: 30512

American (AMR) AF: 0.00389 AC: 167 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24932

East Asian (EAS) AF: 0.00408 AC: 157 AN: 38470

South Asian (SAS) AF: 0.0371 AC: 3041 AN: 81972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39568

Middle Eastern (MID) AF: 0.00616 AC: 24 AN: 3896

European-Non Finnish (NFE) AF: 0.000146 AC: 143 AN: 980078

Other (OTH) AF: 0.00754 AC: 415 AN: 55044

GnomAD4 genome AF: 0.0173 AC: 2627 AN: 152286 Hom.: 87 Cov.: 33 AF XY: 0.0173 AC XY: 1289 AN XY: 74452

African (AFR) AF: 0.0542 AC: 2251 AN: 41548

American (AMR) AF: 0.00712 AC: 109 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00619 AC: 32 AN: 5166

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68032

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0117 Hom.: 13

Bravo AF: 0.0189

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.51
PhyloP100		-0.46
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: rs7691824; hg19: chr4-6297017;