8-31088887-C-A

Position:

• chr8-31088887-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.1577-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,607,294 control chromosomes in the GnomAD database, including 3,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (509 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3036 hom.)
• Consequence: WRN NM_000553.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3898
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.54

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 8-31088887-C-A is Benign according to our data. Variant chr8-31088887-C-A is described in ClinVar as [Benign]. Clinvar id is 130753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31088887-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.1577-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.1577-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000553.6	P1
WRN	ENST00000521620.5	n.278-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
WRN	ENST00000650667.1	c.*1191-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11674 AN: 151838 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.0697

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0686

GnomAD3 exomes AF: 0.0566 AC: 13833 AN: 244582 Hom.: 499 AF XY: 0.0566 AC XY: 7473 AN XY: 131996

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.0208

Gnomad SAS exome AF: 0.0750

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0616 AC: 89699 AN: 1455338 Hom.: 3036 Cov.: 31 AF XY: 0.0621 AC XY: 44901 AN XY: 723534

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0446

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.0737

Gnomad4 FIN exome AF: 0.0662

Gnomad4 NFE exome AF: 0.0616

Gnomad4 OTH exome AF: 0.0608

GnomAD4 genome AF: 0.0770 AC: 11694 AN: 151956 Hom.: 509 Cov.: 32 AF XY: 0.0756 AC XY: 5616 AN XY: 74282

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0453

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.0697

Gnomad4 NFE AF: 0.0600

Gnomad4 OTH AF: 0.0688

Alfa AF: 0.0589 Hom.: 571

Bravo AF: 0.0765

Asia WGS AF: 0.0620 AC: 216 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	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. -

Wiskott-Aldrich syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.39
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.050		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: rs3087409; hg19: chr8-30946403; COSMIC: COSV53297612;