rs4987239

chr8-31064454-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):c.355+20A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,612,694 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (184 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2742 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.140

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-31064454-A-T is Benign according to our data. Variant chr8-31064454-A-T is described in ClinVar as [Benign]. Clinvar id is 256709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31064454-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.355+20A>T		intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.355+20A>T		intron_variant		1	NM_000553.6	P1
WRN	ENST00000650667.1	c.210-461A>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6804 AN: 152122 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0496 AC: 12456 AN: 251284 Hom.: 404 AF XY: 0.0519 AC XY: 7047 AN XY: 135836

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0213

Gnomad SAS exome AF: 0.0779

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0583 AC: 85146 AN: 1460454 Hom.: 2742 Cov.: 31 AF XY: 0.0592 AC XY: 42992 AN XY: 726572

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.0752

Gnomad4 FIN exome AF: 0.0664

Gnomad4 NFE exome AF: 0.0613

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0447 AC: 6806 AN: 152240 Hom.: 184 Cov.: 33 AF XY: 0.0451 AC XY: 3358 AN XY: 74442

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0305

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.0695

Gnomad4 NFE AF: 0.0596

Gnomad4 OTH AF: 0.0432

Alfa AF: 0.0508 Hom.: 35

Bravo AF: 0.0394

Asia WGS AF: 0.0550 AC: 191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

- -

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	-0.83
Cadd	Benign	1.4
Dann	Benign	0.54

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: rs4987239; hg19: chr8-30921970; COSMIC: COSV53301844;