rs369276959

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_000553.6(WRN):​c.4191G>A​(p.Glu1397Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000783 in 1,609,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

WRN
NM_000553.6 splice_region, synonymous

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Likely benign criteria provided, single submitter B:2O:2

Conservation

PhyloP100: 5.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 8-31167230-G-A is Benign according to our data. Variant chr8-31167230-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135442.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WRNNM_000553.6 linkuse as main transcriptc.4191G>A p.Glu1397Glu splice_region_variant, synonymous_variant 34/35 ENST00000298139.7 NP_000544.2 Q14191
WRNXM_011544639.4 linkuse as main transcriptc.4110G>A p.Glu1370Glu splice_region_variant, synonymous_variant 33/34 XP_011542941.1
WRNXM_011544640.2 linkuse as main transcriptc.2592G>A p.Glu864Glu splice_region_variant, synonymous_variant 22/23 XP_011542942.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkuse as main transcriptc.4191G>A p.Glu1397Glu splice_region_variant, synonymous_variant 34/351 NM_000553.6 ENSP00000298139.5 Q14191

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
151960
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000185
AC:
46
AN:
248208
Hom.:
0
AF XY:
0.000201
AC XY:
27
AN XY:
134538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000204
Gnomad ASJ exome
AF:
0.00259
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000107
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000755
AC:
110
AN:
1457650
Hom.:
0
Cov.:
31
AF XY:
0.0000772
AC XY:
56
AN XY:
725266
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00257
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.000183
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
151960
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74234
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.000106
EpiCase
AF:
0.000219
EpiControl
AF:
0.0000595

ClinVar

Significance: Likely benign
Submissions summary: Benign:2Other:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Werner syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024- -
WRN-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 25, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
not provided Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Likely benign and reported on 03-23-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
20
DANN
Benign
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.90
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.38
Position offset: -18
DS_DL_spliceai
0.90
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369276959; hg19: chr8-31024746; API