rs11574311

Variant names:

• chr8-31119144-T-C
• rs11574311
• NM_000553.6:c.2449-1099T>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.2449-1099T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 151,882 control chromosomes in the GnomAD database, including 2,123 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 0.16 (2123 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.2449-1099T>C		intron_variant	Intron 20 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.2449-1099T>C		intron_variant	Intron 20 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.1082-1099T>C		intron_variant	Intron 8 of 22	1
WRN	ENST00000650667.1	n.*2063-1099T>C		intron_variant	Intron 19 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24531 AN: 151764 Hom.: 2117 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.162 AC: 24554 AN: 151882 Hom.: 2123 Cov.: 32 AF XY: 0.163 AC XY: 12125 AN XY: 74278

African (AFR) AF: 0.109 AC: 4537 AN: 41488

American (AMR) AF: 0.145 AC: 2205 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 648 AN: 3456

East Asian (EAS) AF: 0.112 AC: 579 AN: 5174

South Asian (SAS) AF: 0.255 AC: 1228 AN: 4820

European-Finnish (FIN) AF: 0.203 AC: 2145 AN: 10568

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12675 AN: 67832

Other (OTH) AF: 0.165 AC: 348 AN: 2106

Alfa AF: 0.178 Hom.: 423

Bravo AF: 0.153

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11574311; hg19: chr8-30976660;