8-31147397-C-A

Variant names:

• chr8-31147397-C-A
• rs121908447
• NM_000553.6:c.3493C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000553.6(WRN):​c.3493C>A​(p.Gln1165Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1165P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19
• 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3493C>A	p.Gln1165Lys	missense	Exon 30 of 35	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.3493C>A	p.Gln1165Lys	missense	Exon 30 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.2126C>A		non_coding_transcript_exon	Exon 18 of 23
	WRN	ENST00000966176.1		c.3508C>A	p.Gln1170Lys	missense	Exon 30 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
PhyloP100		6.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Benign	0.070	T
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.49
MutPred		0.54		Gain of catalytic residue at Q1165 (P = 0.0244)
MVP		0.75
MPC		0.44
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.61
Mutation Taster		=51/49	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: rs121908447; hg19: chr8-31004913;