8-31125000-G-C

Position:

• chr8-31125000-G-C

Variant summary

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

The ENST00000298139.7(WRN):​c.2825G>C​(p.Arg942Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000116 in 1,459,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R942K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: WRN ENST00000298139.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75

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.2825G>C	p.Arg942Thr	missense_variant, splice_region_variant	23/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.2825G>C	p.Arg942Thr	missense_variant, splice_region_variant	23/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000521620.5	n.1458G>C		splice_region_variant, non_coding_transcript_exon_variant	11/23	1
WRN	ENST00000650667.1	c.*2439G>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	22/34			ENSP00000498593
WRN	ENST00000520169.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250850 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1459798 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Aug 28, 2023

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 942 of the WRN protein (p.Arg942Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs772600753, gnomAD 0.002%). 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: 458431). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 23, but is expected to preserve the integrity of the reading-frame (Invitae). 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	0.16
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.0022
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.16
Sift	Benign	0.046	D
Sift4G	Benign	0.067	T
Polyphen		0.39	B
Vest4		0.43
MutPred		0.47		Gain of phosphorylation at R942 (P = 0.0528);
MVP		0.60
MPC		0.33
ClinPred		0.90	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.25
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772600753; hg19: chr8-30982516;