chr8-31088887-C-A

Position:

chr8-31088887-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1577-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
WRN	ENST00000298139.7 linkuse as main transcript	c.1577-3C>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_000553.6	P1
WRN	ENST00000521620.5 linkuse as main transcript	n.278-3C>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	1
WRN	ENST00000650667.1 linkuse as main transcript	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0621

AC XY:

44901

AN XY:

723534

show subpopulations

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.:

AF XY:

0.0756

AC XY:

5616

AN XY:

74282

show subpopulations

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

LINK: link

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

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

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