chr8-31141607-G-A

Position:

• chr8-31141607-G-A

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.3138+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,613,658 control chromosomes in the GnomAD database, including 165,330 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 0.46 (16495 hom., cov: 30)
  • Exomes 𝑓: 0.45 (148835 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.618

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-31141607-G-A is Benign according to our data. Variant chr8-31141607-G-A is described in ClinVar as [Benign]. Clinvar id is 130755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31141607-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.3138+7G>A		splice_region_variant, intron_variant		ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3138+7G>A		splice_region_variant, intron_variant		1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.1771+7G>A		splice_region_variant, intron_variant		1
WRN	ENST00000650667.1	n.*2752+7G>A		splice_region_variant, intron_variant				ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69854 AN: 151726 Hom.: 16466 Cov.: 30

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.454 AC: 114078 AN: 251362 Hom.: 26880 AF XY: 0.445 AC XY: 60417 AN XY: 135862

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.640

Gnomad SAS exome AF: 0.323

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.448 AC: 654666 AN: 1461814 Hom.: 148835 Cov.: 57 AF XY: 0.443 AC XY: 322115 AN XY: 727208

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.444

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.461 AC: 69937 AN: 151844 Hom.: 16495 Cov.: 30 AF XY: 0.456 AC XY: 33873 AN XY: 74216

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.618

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.443

Gnomad4 OTH AF: 0.461

Alfa AF: 0.448 Hom.: 6519

Bravo AF: 0.480

Asia WGS AF: 0.479 AC: 1664 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Werner syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 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	-0.89
CADD	Benign	0.66
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0
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: rs2737335; hg19: chr8-30999123;