rs113993961

Positions:

chr8-31141680-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000553.6(WRN):c.3139-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000217 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

WRN
NM_000553.6 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:2

Conservation

PhyloP100: 6.50

Variant links:

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN links:

WRN (HGNC:):

WRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.5, offset of 5, new splice context is: ttttgcttttaatacggtAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-31141680-G-C is Pathogenic according to our data. Variant chr8-31141680-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 5447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31141680-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.3139-1G>C		splice_acceptor_variant, intron_variant		ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.3139-1G>C	splice_acceptor_variant, intron_variant	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 linkuse as main transcript	n.1772-1G>C	splice_acceptor_variant, intron_variant	1
WRN	ENST00000650667.1 linkuse as main transcript	n.*2753-1G>C	splice_acceptor_variant, intron_variant			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251348

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000857

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werner syndrome

Pathogenic:4Other:1

not provided, no classification provided	literature only	GeneReviews	-	Founder variant in the Japanese population; accounts for approximately 60% of variants in affected persons in this group. Results in exon 26 skipping. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change affects an acceptor splice site in intron 25 of the WRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993961, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Werner syndrome (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). It is commonly reported in individuals of Japanese ancestry (PMID: 8602509, 10347997, 16673358, 20657174, 27559010). ClinVar contains an entry for this variant (Variation ID: 5447). Studies have shown that disruption of this splice site alters WRN gene expression (PMID: 10543396). Studies have shown that disruption of this splice site results in skipping of exon 26 and introduces a premature termination codon (PMID: 8602509; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The WRN c.3139-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.3139-1G>C variant is reported to be the second most common variant seen in Japanese patients with Werner syndrome due to a founder effect in the Japanese population (Matsumoto et al. 1997; Huang et al. 2006). Across a selection of the available literature, the c.3139-1G>C variant has been identified in a homozygous state in 45 patients, in a compound heterozygous state in eight patients, and in a heterozygous state in eight patients (Yu et al. 1996; Matsumoto et al. 1997; Satoh et al. 1999; Huang et al. 2006). The variant was also detected in a heterozygous state in six of 1076 controls and is reported at a frequency of 0.00023 in the East Asian population of the Exome Aggregation Consortium, although this is based on only two alleles in a region of good sequencing coverage so the variant is presumed to be rare in the general population. RT-PCR experiments in patient cells have shown the variant results in the skipping of exon 26 (Yu et al. 1996). Due to the supporting evidence from the literature and the potential impact of splice acceptor variants, the c.3139-1G>C variant is classified as pathogenic for Werner syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2006	- -

not provided

Other:1

not provided, no classification provided

literature only

SNPedia

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.80

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over