chr4-6302180-G-GGAC

Position:

• chr4-6302180-G-GGAC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM4_Supporting PP3 BP6_Very_Strong BS2

The NM_006005.3(WFS1):​c.2390_2392dupACG​(p.Asp797dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,612,554 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: WFS1 NM_006005.3 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.37

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM1: In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
• PM4: Nonframeshift variant in NON repetitive region in NM_006005.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 4-6302180-G-GGAC is Benign according to our data. Variant chr4-6302180-G-GGAC is described in ClinVar as [Likely_benign]. Clinvar id is 45454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2390_2392dupACG	p.Asp797dup	disruptive_inframe_insertion	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2390_2392dupACG	p.Asp797dup	disruptive_inframe_insertion	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2390_2392dupACG	p.Asp797dup	disruptive_inframe_insertion	8/8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152240 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00195 AC: 478 AN: 245616 Hom.: 3 AF XY: 0.00246 AC XY: 329 AN XY: 133850

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00858

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00144 AC: 2109 AN: 1460194 Hom.: 14 Cov.: 99 AF XY: 0.00174 AC XY: 1267 AN XY: 726382

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00919

Gnomad4 FIN exome AF: 0.000827

Gnomad4 NFE exome AF: 0.000947

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152360 Hom.: 1 Cov.: 34 AF XY: 0.00150 AC XY: 112 AN XY: 74504

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00189

Bravo AF: 0.000861

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	This variant is associated with the following publications: (PMID: 25740874, 12754709) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	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	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2015

p.Asp797dup in exon 8 of WFS1: This variant is not expected to have clinical sig nificance it has been identified in 0.7% (124/16292) of South Asian chromosomes, with two homozygote individuals, by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs397517197). -

WFS1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517197; hg19: chr4-6303907;