rs28937890

chr4-6301966-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_006005.3(WFS1):c.2171C>T(p.Pro724Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P724S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.43

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301965-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379865.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-6301966-C-T is Pathogenic according to our data. Variant chr4-6301966-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4509.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}. Variant chr4-6301966-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2171C>T	p.Pro724Leu	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2171C>T	p.Pro724Leu	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2171C>T	p.Pro724Leu	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1949G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000322 AC: 8 AN: 248128 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134866

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1460444 Hom.: 0 Cov.: 99 AF XY: 0.0000275 AC XY: 20 AN XY: 726508

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7 AN XY: 74384

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000801 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 04, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been associated with autosomal recessive Wolfram Syndrome (PMID: 9771706, 24890733) and autosomal recessive Optic Atrophy (PMID: 27395765). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abrogates the ability of WFS1 to negatively regulate ATF6-alpha, a transcription factor that is responsible for upregulating stress signaling targets, thereby causing ER-stress mediated apoptosis in pancreatic beta-cells (PMID: 20160352). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2018	The WFS1 c.2171C>T; p.Pro724Leu variant (rs28937890) has been previously observed as a homozygote in a pair of siblings from a consanguineous Japanese family with a Wolfram syndrome phenotype (minimally, juvenile-onset diabetes mellitus and optic atrophy; Inoue 1998). Numerous functional studies have demonstrated that this variant effects WFS1 protein stability (Hofmann 2006), localization (Fonseca 2005), increased tendency for aggregation (De Franco 2017), and interactions with ATF6 (Fonseca 2010). This variant is found in the general population with an overall allele frequency of 0.003% (8/243,604 alleles) in the Genome Aggregation Database. Based on the available information, the clinical significance of this variant cannot be determined with certainty. De Franco E et al. Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053. Fonseca SG et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005 Nov 25;280(47):39609-15 Fonseca SG et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010 Mar;120(3):744-55. Hofmann S and Bauer M. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Inoue H et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WFS1 function (PMID: 16195229, 16806192). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 4509). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 9771706, 24890733). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937890, gnomAD 0.03%). This sequence change replaces proline, a(n) neutral and non-polar amino acid, with leucine, a(n) neutral and non-polar amino acid, at codon 724 of the WFS1 protein (p.Pro724Leu). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	Published functional studies demonstrate a damaging effect resulting in abnormal ERSE reporter activity in pancreatic beta-cells (Fonseca et al., 2005; De Franco et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22983116, 20160352, 11709537, 11317350, 12955714, 24424032, 26435059, 16806192, 21454619, 28468959, 24227685, 27434582, 11244483, 34406036, 34848728, 37185285, 12618560, 24890733, 30245029, 9771706, 33663443, 27395765, 34404380, 36208030, 25211237, 16195229) -

Wolfram syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-9.9	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MVP		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.94

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: rs28937890; hg19: chr4-6303693;