rs1284409960
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000553.6(WRN):c.3408dup(p.Ala1137SerfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
WRN
NM_000553.6 frameshift
NM_000553.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0340
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-31147072-G-GA is Pathogenic according to our data. Variant chr8-31147072-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.3408dup | p.Ala1137SerfsTer28 | frameshift_variant | 29/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.3408dup | p.Ala1137SerfsTer28 | frameshift_variant | 29/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.2041dup | non_coding_transcript_exon_variant | 17/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*3022dup | 3_prime_UTR_variant, NMD_transcript_variant | 28/34 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135828
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727022
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Werner syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 458452). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ala1137Serfs*28) in the WRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at