5-140114334-AG-AGG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005859.5(PURA):c.159dupG(p.Leu54AlafsTer147) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_005859.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PURA | ENST00000331327.5 | c.159dupG | p.Leu54AlafsTer147 | frameshift_variant | Exon 1 of 1 | 6 | NM_005859.5 | ENSP00000332706.3 | ||
PURA | ENST00000651386.1 | c.159dupG | p.Leu54AlafsTer147 | frameshift_variant | Exon 2 of 2 | ENSP00000499133.1 | ||||
PURA | ENST00000505703.2 | c.159dupG | p.Leu54AlafsTer53 | frameshift_variant | Exon 2 of 2 | 3 | ENSP00000498560.1 | |||
PURA | ENST00000502351.1 | c.*74_*75insG | downstream_gene_variant | 2 | ENSP00000498760.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 7.77e-7 AC: 1AN: 1287560Hom.: 0 Cov.: 33 AF XY: 0.00000157 AC XY: 1AN XY: 636982
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Pathogenic:4
This sequence change creates a premature translational stop signal (p.Leu54Alafs*147) in the PURA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 269 amino acid(s) of the PURA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PURA-related conditions (PMID: 32581362). ClinVar contains an entry for this variant (Variation ID: 432233). This variant disrupts a region of the PURA protein in which other variant(s) (p.Tyr240*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
The PURA c.159dup (p.Leu54Alafs*147) variant has been reported as occurring de novo in four individuals affected with PURA-related neurodevelopmental disorders (PURA-NDDs) (Dai W et al., PMID: 36376392). This variant has been reported in the ClinVar database as a pathogenic variant by six submitters and as a likely pathogenic variant by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by inserting one nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
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Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000432233, PMID:32581362). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:3
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 269 amino acids are lost and replaced with 146 incorrect amino acids.; Not observed in large population cohorts (Lek et al., 2016); Reported in a large cohort of individuals with rare disease, but clinical information is not provided (Turro et al., 2020); This variant is associated with the following publications: (PMID: 32581362) -
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PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation Pathogenic:1
The p.Leu54fs variant in PURA has not been previously reported in individuals wi th severe neonatal hypotonia-seizures-encephalopathy syndrome. Data from large p opulation studies is insufficient to assess the frequency of this variant. The p .Leu54fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 54 and leads to a premature terminatio n codon 147 amino acids downstream. This gene contains a single exon, so the alt ered transcript is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Heterozygous truncating variants in the PURA gene are strongly associated with severe neonatal hypotonia-seizures-encephalopathy syndr ome, with the all causative variants reported to date occuring de novo. In summa ry, the p.Leu54fs variant meets criteria to be classified as pathogenic for seve re neonatal hypotonia-seizures-encephalopathy syndrome based on its predicted im pact to the protein. -
Intellectual disability Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at