rs201172985

Variant names:

• chr8-31087849-G-T
• rs201172985
• NM_000553.6:c.1505G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000553.6(WRN):​c.1505G>T​(p.Gly502Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G502R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.73

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05540356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.1505G>T	p.Gly502Val	missense_variant	Exon 12 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1505G>T	p.Gly502Val	missense_variant	Exon 12 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.206G>T		non_coding_transcript_exon_variant	Exon 1 of 23	1
WRN	ENST00000650667.1	n.*1119G>T		non_coding_transcript_exon_variant	Exon 11 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*1119G>T		3_prime_UTR_variant	Exon 11 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250800 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461454 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727026

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33466

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44712

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26124

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39666

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86252

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53274

Gnomad4 NFE exome AF: 0.0000477 AC: 53 AN: 1111804

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240685 AN: 0.0000240685

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000882 AC: 0.0000882145 AN: 0.0000882145

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1505G>T (p.G502V) alteration is located in exon 12 (coding exon 11) of the WRN gene. This alteration results from a G to T substitution at nucleotide position 1505, causing the glycine (G) at amino acid position 502 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Werner syndrome Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the WRN protein (p.Gly502Val). This variant is present in population databases (rs201172985, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 404021). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

WRN-related disorder Uncertain:1

Jan 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The WRN c.1505G>T variant is predicted to result in the amino acid substitution p.Gly502Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/404021/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.19
DANN	Benign	0.56
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.072
Sift	Benign	0.31	T
Sift4G	Uncertain	0.038	D
Polyphen		0.21	B
Vest4		0.16
MutPred		0.18		Gain of methylation at K506 (P = 0.0877);
MVP		0.33
MPC		0.093
ClinPred		0.074	T
GERP RS		-8.5
Varity_R		0.053
gMVP		0.45
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201172985; hg19: chr8-30945365;