rs190364546

Positions:

• chr8-31141520-C-A
• chr8-31141520-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000298139.7(WRN):​c.3058C>A​(p.Arg1020Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. 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. R1020H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN ENST00000298139.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.3058C>A	p.Arg1020Ser	missense_variant	25/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3058C>A	p.Arg1020Ser	missense_variant	25/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000521620.5	n.1691C>A		non_coding_transcript_exon_variant	13/23	1
WRN	ENST00000650667.1	c.*2672C>A		3_prime_UTR_variant, NMD_transcript_variant	24/34			ENSP00000498593

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.20
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.73	P
Vest4		0.44
MutPred		0.74		Loss of MoRF binding (P = 0.0404);
MVP		0.62
MPC		0.36
ClinPred		0.66	D
GERP RS		3.2
Varity_R		0.41
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-30999036;