rs6994361

Variant names:

• chr8-31161169-C-T
• rs6994361
• NM_000553.6:c.3982+3639C>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.3982+3639C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 151,974 control chromosomes in the GnomAD database, including 28,795 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 0.61 (28795 hom., cov: 31)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114
• Publications: 2 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.696 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.3982+3639C>T		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.3982+3639C>T		intron	N/A	ENSP00000298139.5
	WRN	ENST00000521620.5	TSL:1	n.2615+3639C>T		intron	N/A
	WRN	ENST00000650667.1		n.*3596+3639C>T		intron	N/A	ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92968 AN: 151856 Hom.: 28771 Cov.: 31

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.604

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

GnomAD4 genome AF: 0.612 AC: 93034 AN: 151974 Hom.: 28795 Cov.: 31 AF XY: 0.615 AC XY: 45658 AN XY: 74290

African (AFR) AF: 0.621 AC: 25743 AN: 41430

American (AMR) AF: 0.520 AC: 7929 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1969 AN: 3472

East Asian (EAS) AF: 0.384 AC: 1983 AN: 5168

South Asian (SAS) AF: 0.716 AC: 3451 AN: 4822

European-Finnish (FIN) AF: 0.712 AC: 7525 AN: 10568

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42326 AN: 67946

Other (OTH) AF: 0.603 AC: 1273 AN: 2112

Alfa AF: 0.613 Hom.: 121759

Bravo AF: 0.592

Asia WGS AF: 0.543 AC: 1891 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.7
DANN	Benign	0.52
PhyloP100		0.11
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: rs6994361; hg19: chr8-31018685;