8-31058454-G-GA
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000553.6(WRN):c.15dupA(p.Leu6IlefsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000553.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.15dupA | p.Leu6IlefsTer12 | frameshift_variant | Exon 2 of 35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000650667.1 | n.15dupA | non_coding_transcript_exon_variant | Exon 2 of 34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460392Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726498
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151932Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74190
ClinVar
Submissions by phenotype
Werner syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Leu6Ilefs*12) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1070898). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at