8-31065004-C-A

Position:

• chr8-31065004-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000553.6(WRN):​c.445C>A​(p.Arg149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1878928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.445C>A	p.Arg149Ser	missense_variant	5/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.445C>A	p.Arg149Ser	missense_variant	5/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000650667.1	c.*59C>A		3_prime_UTR_variant, NMD_transcript_variant	4/34			ENSP00000498593

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.094
Sift	Benign	0.83	T
Sift4G	Benign	0.77	T
Polyphen		0.42	B
Vest4		0.25
MutPred		0.67		Loss of stability (P = 0.0584);
MVP		0.65
MPC		0.088
ClinPred		0.36	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs752693894; hg19: chr8-30922520;