NM_000553.6:c.724+812A>T

Variant names:

• chr8-31069139-A-T
• rs11574212
• NM_000553.6:c.724+812A>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.724+812A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 152,334 control chromosomes in the GnomAD database, including 110 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 0.031 (110 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 3 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 = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.724+812A>T		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.724+812A>T		intron_variant	Intron 7 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1	c.19+812A>T		intron_variant	Intron 1 of 3			ENSP00000498779.1
WRN	ENST00000650667.1	n.*338+812A>T		intron_variant	Intron 6 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4657 AN: 152216 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.0854

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0273

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

GnomAD4 genome AF: 0.0306 AC: 4660 AN: 152334 Hom.: 110 Cov.: 32 AF XY: 0.0317 AC XY: 2360 AN XY: 74486

African (AFR) AF: 0.00748 AC: 311 AN: 41580

American (AMR) AF: 0.0394 AC: 602 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.0854 AC: 443 AN: 5190

South Asian (SAS) AF: 0.0669 AC: 323 AN: 4830

European-Finnish (FIN) AF: 0.0370 AC: 393 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0357 AC: 2430 AN: 68032

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0287 Hom.: 11

Bravo AF: 0.0293

Asia WGS AF: 0.0880 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.83
DANN	Benign	0.54
PhyloP100		-0.31
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: rs11574212; hg19: chr8-30926655;