rs3821945

chr4-6302391-G-Achr4-6302391-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_006005.3(WFS1):c.2596G>A(p.Asp866Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,613,118 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D866Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00078 (12 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 5.85

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009685487).
• BP6: Variant 4-6302391-G-A is Benign according to our data. Variant chr4-6302391-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178655.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=6, Uncertain_significance=1}. Variant chr4-6302391-G-A is described in Lovd as [Benign]. Variant chr4-6302391-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00147 (224/152384) while in subpopulation EAS AF= 0.02 (104/5188). AF 95% confidence interval is 0.0169. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2596G>A	p.Asp866Asn	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2596G>A	p.Asp866Asn	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2596G>A	p.Asp866Asn	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1524C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152266 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00186 AC: 465 AN: 250194 Hom.: 7 AF XY: 0.00173 AC XY: 234 AN XY: 135632

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0192

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000779 AC: 1138 AN: 1460734 Hom.: 12 Cov.: 87 AF XY: 0.000762 AC XY: 554 AN XY: 726710

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0178

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000701

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152384 Hom.: 1 Cov.: 35 AF XY: 0.00160 AC XY: 119 AN XY: 74522

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.00181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asp866Asn in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 6.1% (5/82) of chromosomes from a pop ulation in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs38219 45). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2015	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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	WFS1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Wolfram syndrome 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs3821945 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 25, 2019	- -

WFS1-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 01, 2017

ACMG Criteria:PP3 (6 predictors), BP4 (5 predictors), BP6 (called benign by Partners, GeneDx and Emory) -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.27	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.95	P;P
Vest4		0.39
MVP		0.97
ClinPred		0.0084	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs3821945; hg19: chr4-6304118; COSMIC: COSV56988561; COSMIC: COSV56988561;