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
NM_000553.6 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.01
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]
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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 |
---|---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.4191G>A | p.Glu1397Glu | splice_region_variant, synonymous_variant | 34/35 | ENST00000298139.7 | NP_000544.2 | |
WRN | XM_011544639.4 | c.4110G>A | p.Glu1370Glu | splice_region_variant, synonymous_variant | 33/34 | XP_011542941.1 | ||
WRN | XM_011544640.2 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.4191G>A | p.Glu1397Glu | splice_region_variant, synonymous_variant | 34/35 | 1 | NM_000553.6 | ENSP00000298139.5 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 151960Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000185 AC: 46AN: 248208Hom.: 0 AF XY: 0.000201 AC XY: 27AN XY: 134538
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GnomAD4 exome AF: 0.0000755 AC: 110AN: 1457650Hom.: 0 Cov.: 31 AF XY: 0.0000772 AC XY: 56AN XY: 725266
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GnomAD4 genome AF: 0.000105 AC: 16AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74234
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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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | - - |
WRN-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 25, 2024 | This 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 provided | reference population | ITMI | Sep 19, 2013 | - - |
not provided Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -18
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at