8-31075099-C-G

Variant names:

• chr8-31075099-C-G
• rs2725383
• NM_000553.6:c.725-1074C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):​c.725-1074C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 152,100 control chromosomes in the GnomAD database, including 44,911 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 0.77 (44911 hom., cov: 31)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.725-1074C>G		intron_variant	Intron 7 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.725-1074C>G		intron_variant	Intron 7 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1	c.20-1074C>G		intron_variant	Intron 1 of 3			ENSP00000498779.1
WRN	ENST00000650667.1	n.*339-1074C>G		intron_variant	Intron 6 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.765 AC: 116317 AN: 151982 Hom.: 44878 Cov.: 31

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.768

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

GnomAD4 genome AF: 0.765 AC: 116401 AN: 152100 Hom.: 44911 Cov.: 31 AF XY: 0.766 AC XY: 57003 AN XY: 74368

African (AFR) AF: 0.666 AC: 27591 AN: 41454

American (AMR) AF: 0.819 AC: 12527 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 2842 AN: 3468

East Asian (EAS) AF: 0.875 AC: 4517 AN: 5164

South Asian (SAS) AF: 0.746 AC: 3603 AN: 4828

European-Finnish (FIN) AF: 0.790 AC: 8359 AN: 10578

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54333 AN: 67996

Other (OTH) AF: 0.770 AC: 1625 AN: 2110

Alfa AF: 0.774 Hom.: 5666

Bravo AF: 0.766

Asia WGS AF: 0.802 AC: 2788 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.12
DANN	Benign	0.69
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2725383; hg19: chr8-30932615;