4-6269689-G-T

Variant names:

• chr4-6269689-G-T
• rs4273545
• NM_006005.3:c.-331G>T

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.-331G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 152,038 control chromosomes in the GnomAD database, including 24,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.56 (24678 hom., cov: 34)
• Consequence: WFS1 NM_006005.3 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.398
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 4-6269689-G-T is Benign according to our data. Variant chr4-6269689-G-T is described in ClinVar as Benign. ClinVar VariationId is 684340.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.-331G>T		upstream_gene	N/A	NP_005996.2
	WFS1	NM_001145853.1		c.-327G>T		upstream_gene	N/A	NP_001139325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.-331G>T		upstream_gene	N/A	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.-327G>T		upstream_gene	N/A	ENSP00000423337.1
	WFS1	ENST00000673991.1		c.-327G>T		upstream_gene	N/A	ENSP00000501033.1

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84635 AN: 151922 Hom.: 24661 Cov.: 34

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.585

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.557 AC: 84684 AN: 152038 Hom.: 24678 Cov.: 34 AF XY: 0.562 AC XY: 41746 AN XY: 74304

African (AFR) AF: 0.423 AC: 17561 AN: 41506

American (AMR) AF: 0.650 AC: 9935 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2300 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4792 AN: 5138

South Asian (SAS) AF: 0.666 AC: 3205 AN: 4810

European-Finnish (FIN) AF: 0.547 AC: 5790 AN: 10578

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.578 AC: 39269 AN: 67932

Other (OTH) AF: 0.588 AC: 1242 AN: 2114

Alfa AF: 0.559 Hom.: 3119

Bravo AF: 0.560

Asia WGS AF: 0.762 AC: 2651 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.7
DANN	Benign	0.51
PhyloP100		0.40
PromoterAI		0.010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4273545; hg19: chr4-6271416;