chr4-6292013-G-A

Position:

• chr4-6292013-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006005.3(WFS1):​c.712+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,595,556 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (19 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-6292013-G-A is Benign according to our data. Variant chr4-6292013-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6292013-G-A is described in Lovd as [Likely_benign]. Variant chr4-6292013-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.712+16G>A		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.712+16G>A		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.712+16G>A		intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152164 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00345 AC: 742 AN: 214856 Hom.: 9 AF XY: 0.00375 AC XY: 436 AN XY: 116376

Gnomad AFR exome AF: 0.000538

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00267 AC: 3853 AN: 1443274 Hom.: 19 Cov.: 36 AF XY: 0.00281 AC XY: 2014 AN XY: 716402

Gnomad4 AFR exome AF: 0.000422

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.0186

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00657

Gnomad4 FIN exome AF: 0.0000393

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152282 Hom.: 3 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74448

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00465 Hom.: 3

Bravo AF: 0.00230

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	WFS1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2017	- -

Wolfram syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs71524367 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs71524367; hg19: chr4-6293740;