8-31078840-G-T

Variant names:

• chr8-31078840-G-T
• rs2553268
• NM_000553.6:c.840-2027G>T

Variant summary

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

The NM_000553.6(WRN):​c.840-2027G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 152,064 control chromosomes in the GnomAD database, including 34,783 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 0.67 (34783 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 14 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.840-2027G>T		intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.840-2027G>T		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.840-2027G>T		intron	N/A	ENSP00000636235.1
	WRN	ENST00000860283.1		c.840-2027G>T		intron	N/A	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101830 AN: 151946 Hom.: 34761 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.670 AC: 101902 AN: 152064 Hom.: 34783 Cov.: 32 AF XY: 0.675 AC XY: 50200 AN XY: 74318

African (AFR) AF: 0.540 AC: 22387 AN: 41464

American (AMR) AF: 0.757 AC: 11568 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2535 AN: 3468

East Asian (EAS) AF: 0.862 AC: 4452 AN: 5162

South Asian (SAS) AF: 0.659 AC: 3178 AN: 4826

European-Finnish (FIN) AF: 0.742 AC: 7841 AN: 10570

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47648 AN: 67986

Other (OTH) AF: 0.663 AC: 1397 AN: 2108

Alfa AF: 0.692 Hom.: 51472

Bravo AF: 0.669

Asia WGS AF: 0.755 AC: 2624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.1
DANN	Benign	0.70
PhyloP100		0.064
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: rs2553268; hg19: chr8-30936356;