rs1060500066

Positions:

• chr8-31083700-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000553.6(WRN):​c.1271A>G​(p.His424Arg) variant causes a missense, splice region 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense, splice_region
• Scores: Splicing: ADA: 0.00001861
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04626289).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.1271A>G	p.His424Arg	missense_variant, splice_region_variant	10/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1271A>G	p.His424Arg	missense_variant, splice_region_variant	10/35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1	c.565-1466A>G		intron_variant				ENSP00000498779.1
WRN	ENST00000650667.1	n.*885A>G		splice_region_variant, non_coding_transcript_exon_variant	9/34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*885A>G		3_prime_UTR_variant	9/34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 424 of the WRN protein (p.His424Arg). 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: 404003). 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	0.071
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.3
DANN	Benign	0.32
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.023
Sift	Benign	0.20	T
Sift4G	Benign	0.34	T
Polyphen		0.072	B
Vest4		0.089
MutPred		0.14		Gain of phosphorylation at S426 (P = 0.0858);
MVP		0.25
MPC		0.077
ClinPred		0.031	T
GERP RS		1.3
Varity_R		0.042
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0060
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: rs1060500066; hg19: chr8-30941216;