rs2725338

Variant names:

• chr8-31042501-G-A
• rs2725338
• NM_000553.6:c.-77+8528G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31042501-G-A
• chr8-31042501-G-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.-77+8528G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0792 in 152,248 control chromosomes in the GnomAD database, including 650 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 0.079 (650 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.-77+8528G>A		intron_variant	Intron 1 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.-77+8528G>A		intron_variant	Intron 1 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000650667.1	n.-77+8528G>A		intron_variant	Intron 1 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12028 AN: 152130 Hom.: 643 Cov.: 32

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0673

Gnomad OTH AF: 0.0688

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

GnomAD4 genome AF: 0.0792 AC: 12054 AN: 152248 Hom.: 650 Cov.: 32 AF XY: 0.0826 AC XY: 6146 AN XY: 74424

African (AFR) AF: 0.0514 AC: 2136 AN: 41560

American (AMR) AF: 0.157 AC: 2399 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1162 AN: 5188

South Asian (SAS) AF: 0.121 AC: 583 AN: 4814

European-Finnish (FIN) AF: 0.0844 AC: 894 AN: 10598

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0673 AC: 4578 AN: 68006

Other (OTH) AF: 0.0686 AC: 145 AN: 2114

Alfa AF: 0.0808 Hom.: 307

Bravo AF: 0.0853

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.45
PhyloP100		0.098
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: rs2725338; hg19: chr8-30900017;