rs1554523021

Variant names:

• chr8-31090858-A-G
• rs1554523021
• NM_000553.6:c.1745A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000553.6(WRN):​c.1745A>G​(p.Gln582Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000553.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.1745A>G	p.Gln582Arg	missense_variant	Exon 15 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1745A>G	p.Gln582Arg	missense_variant	Exon 15 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.378A>G		non_coding_transcript_exon_variant	Exon 3 of 23	1
WRN	ENST00000650667.1	n.*1359A>G		non_coding_transcript_exon_variant	Exon 14 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*1359A>G		3_prime_UTR_variant	Exon 14 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000548 AC: 8 AN: 1459088 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725718

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110500

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000625 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Werner syndrome Uncertain:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 582 of the WRN protein (p.Gln582Arg). This variant is not present in population databases (gnomAD no frequency). 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: 528179). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.73
MPC		0.41
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.83
Mutation Taster		=53/47	polymorphism

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: rs1554523021; hg19: chr8-30948374; COSMIC: COSV53302845;