rs606231162

Positions:

• chr8-31154621-TAGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000553.6(WRN):​c.3690_3693del​(p.Asp1231SerfsTer16) variant causes a splice acceptor, coding sequence change. The variant allele was found at a frequency of 0.00000617 in 1,458,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: WRN NM_000553.6 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.030472202 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 0 (no position change), new splice context is: ctacattaaaaattctgtAGacc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-31154621-TAGAC-T is Pathogenic according to our data. Variant chr8-31154621-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 5446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31154621-TAGAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.3690_3693del	p.Asp1231SerfsTer16	splice_acceptor_variant, coding_sequence_variant	32/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3690_3693del	p.Asp1231SerfsTer16	splice_acceptor_variant, coding_sequence_variant	32/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000521620.5	n.2323_2326del		splice_acceptor_variant, non_coding_transcript_exon_variant	20/23	1
WRN	ENST00000650667.1	c.*3304_*3307del		splice_acceptor_variant, 3_prime_UTR_variant, NMD_transcript_variant	31/34			ENSP00000498593

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246806 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458794 Hom.: 0 AF XY: 0.00000551 AC XY: 4 AN XY: 725578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change creates a premature translational stop signal (p.Asp1231Serfs*16) in the WRN gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs606231162, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Werner syndrome (WS) (PMID: 8602509, 8968742, 16786514). It has also been observed to segregate with disease in related individuals. This variant is also known as 3919–3922 ACAG deletion. ClinVar contains an entry for this variant (Variation ID: 5446). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 7
DS_AL_spliceai		0.98		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231162; hg19: chr8-31012137;