8-31058453-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000553.6(WRN):c.6T>G(p.Ser2Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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.

• PM1: In a modified_residue N-acetylserine (size 0) in uniprot entity WRN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0794684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.6T>G	p.Ser2Arg	missense_variant	2/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.6T>G	p.Ser2Arg	missense_variant	2/35	1	NM_000553.6	P1
WRN	ENST00000650667.1	c.6T>G	p.Ser2Arg	missense_variant, NMD_transcript_variant	2/34

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Werner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2021

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2 of the WRN protein (p.Ser2Arg). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.045
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.011	D
Polyphen		0.019	B
Vest4		0.20
MutPred		0.13		Gain of MoRF binding (P = 0.0115);
MVP		0.30
MPC		0.080
ClinPred		0.063	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.40

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: chr8-30915969;