chr8-31119876-T-C

Variant names:

• chr8-31119876-T-C
• rs4733225
• NM_000553.6:c.2449-367T>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.2449-367T>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
• Publications: 16 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.2449-367T>C		intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.2449-367T>C		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1082-367T>C		intron	N/A
	WRN	ENST00000966176.1		c.2464-367T>C		intron	N/A	ENSP00000636235.1

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

African (AFR) AF: 0.0518 AC: 51 AN: 984

American (AMR) AF: 0.199 AC: 610 AN: 3070

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 292 AN: 1398

East Asian (EAS) AF: 0.222 AC: 572 AN: 2580

South Asian (SAS) AF: 0.214 AC: 1761 AN: 8212

European-Finnish (FIN) AF: 0.255 AC: 633 AN: 2486

Middle Eastern (MID) AF: 0.224 AC: 57 AN: 254

European-Non Finnish (NFE) AF: 0.170 AC: 6218 AN: 36578

Other (OTH) AF: 0.175 AC: 564 AN: 3214

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

African (AFR) AF: 0.0532 AC: 2211 AN: 41522

American (AMR) AF: 0.193 AC: 2930 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1300 AN: 5176

South Asian (SAS) AF: 0.235 AC: 1134 AN: 4816

European-Finnish (FIN) AF: 0.299 AC: 3165 AN: 10574

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12743 AN: 67862

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.183 Hom.: 4524

Bravo AF: 0.151

Asia WGS AF: 0.237 AC: 822 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.7
DANN	Benign	0.53
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.96
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4733225; hg19: chr8-30977392;