rs2725385

chr8-31070630-T-Cchr8-31070630-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):c.724+2303T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 151,544 control chromosomes in the GnomAD database, including 35,237 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (35237 hom., cov: 28)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.724+2303T>C		intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.724+2303T>C		intron_variant		1	NM_000553.6	P1
WRN	ENST00000651642.1	c.19+2303T>C		intron_variant
WRN	ENST00000650667.1	c.*338+2303T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102229 AN: 151426 Hom.: 35218 Cov.: 28

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.675 AC: 102293 AN: 151544 Hom.: 35237 Cov.: 28 AF XY: 0.680 AC XY: 50361 AN XY: 74058

Gnomad4 AFR AF: 0.537

Gnomad4 AMR AF: 0.760

Gnomad4 ASJ AF: 0.739

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.755

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.669

Alfa AF: 0.701 Hom.: 45499

Bravo AF: 0.673

Asia WGS AF: 0.764 AC: 2657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.020
Dann	Benign	0.38

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: rs2725385; hg19: chr8-30928146;