rs754208761
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_000553.6(WRN):c.209+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,606,338 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000553.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.209+5G>A | splice_region_variant, intron_variant | ENST00000298139.7 | NP_000544.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.209+5G>A | splice_region_variant, intron_variant | 1 | NM_000553.6 | ENSP00000298139.5 | ||||
WRN | ENST00000650667.1 | n.209+5G>A | splice_region_variant, intron_variant | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251176Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135782
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1454144Hom.: 0 Cov.: 28 AF XY: 0.00000553 AC XY: 4AN XY: 723934
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
Werner syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change falls in intron 3 of the WRN gene. It does not directly change the encoded amino acid sequence of the WRN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754208761, 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: 576138). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at