7-108472486-TCTTGA-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_001256007.3(PNPLA8):c.2259_2263del(p.Ser753ArgfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,607,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
PNPLA8
NM_001256007.3 frameshift
NM_001256007.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.53
Genes affected
PNPLA8 (HGNC:28900): (patatin like phospholipase domain containing 8) This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0383 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-108472486-TCTTGA-T is Pathogenic according to our data. Variant chr7-108472486-TCTTGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2101064.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA8 | NM_001256007.3 | c.2259_2263del | p.Ser753ArgfsTer9 | frameshift_variant | 11/11 | ENST00000257694.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA8 | ENST00000257694.13 | c.2259_2263del | p.Ser753ArgfsTer9 | frameshift_variant | 11/11 | 1 | NM_001256007.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246072Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133232
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GnomAD4 exome AF: 0.0000213 AC: 31AN: 1455510Hom.: 0 AF XY: 0.0000276 AC XY: 20AN XY: 724046
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 21, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PNPLA8 protein in which other variant(s) (p.Leu759Alafs*4) have been determined to be pathogenic (PMID: 25512002, 29681094). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2101064). This variant has not been reported in the literature in individuals affected with PNPLA8-related conditions. This variant is present in population databases (rs751849953, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ser753Argfs*9) in the PNPLA8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PNPLA8 protein. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at