8-31070630-T-C

Variant names:

• chr8-31070630-T-C
• rs2725385
• NM_000553.6:c.724+2303T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.724+2303T>C		intron	N/A	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.724+2303T>C		intron	N/A	ENSP00000298139.5
	WRN	ENST00000651642.1		c.19+2303T>C		intron	N/A	ENSP00000498779.1
	WRN	ENST00000650667.1		n.*338+2303T>C		intron	N/A	ENSP00000498593.1

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

African (AFR) AF: 0.537 AC: 22156 AN: 41228

American (AMR) AF: 0.760 AC: 11585 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2558 AN: 3460

East Asian (EAS) AF: 0.869 AC: 4452 AN: 5126

South Asian (SAS) AF: 0.660 AC: 3162 AN: 4792

European-Finnish (FIN) AF: 0.755 AC: 7966 AN: 10554

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48119 AN: 67850

Other (OTH) AF: 0.669 AC: 1401 AN: 2094

Alfa AF: 0.696 Hom.: 110951

Bravo AF: 0.673

Asia WGS AF: 0.764 AC: 2657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.020
DANN	Benign	0.38
PhyloP100		-2.3
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: rs2725385; hg19: chr8-30928146;