rs4733225

chr8-31119876-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):c.2449-367T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 210,732 control chromosomes in the GnomAD database, including 3,722 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 (2595 hom., cov: 32)
  • Exomes 𝑓: 0.18 (1127 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.137

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.2449-367T>C		intron_variant		ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.2449-367T>C		intron_variant		1	NM_000553.6	P1
WRN	ENST00000521620.5	n.1082-367T>C		intron_variant, non_coding_transcript_variant		1
WRN	ENST00000650667.1	c.*2063-367T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24965 AN: 151838 Hom.: 2593 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.171

GnomAD4 exome AF: 0.183 AC: 10758 AN: 58776 Hom.: 1127 AF XY: 0.189 AC XY: 5871 AN XY: 30986

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.164 AC: 24965 AN: 151956 Hom.: 2595 Cov.: 32 AF XY: 0.173 AC XY: 12818 AN XY: 74272

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.173

Alfa AF: 0.188 Hom.: 2961

Bravo AF: 0.151

Asia WGS AF: 0.237 AC: 822 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	6.7
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4733225; hg19: chr8-30977392;