chr7-108472473-CAG-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001256007.3(PNPLA8):c.2275_2276del(p.Leu759AlafsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000875 in 1,600,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
PNPLA8
NM_001256007.3 frameshift
NM_001256007.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.08
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 Uncertain_significance. Variant got 5 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 0.0315 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-108472473-CAG-C is Pathogenic according to our data. Variant chr7-108472473-CAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190128.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr7-108472473-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA8 | NM_001256007.3 | c.2275_2276del | p.Leu759AlafsTer4 | frameshift_variant | 11/11 | ENST00000257694.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA8 | ENST00000257694.13 | c.2275_2276del | p.Leu759AlafsTer4 | frameshift_variant | 11/11 | 1 | NM_001256007.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000165 AC: 4AN: 242202Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130890
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GnomAD4 exome AF: 0.00000760 AC: 11AN: 1447946Hom.: 0 AF XY: 0.00000972 AC XY: 7AN XY: 720412
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mitochondrial myopathy-lactic acidosis-deafness syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This variant is present in population databases (rs774184465, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Leu759Alafs*4) in the PNPLA8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the PNPLA8 protein. This premature translational stop signal has been observed in individual(s) with mitochondrial myopathy with lactic acidosis (PMID: 25512002, 29681094). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190128). This variant is also known as c.1975_1976delAG. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2016 | The c.2275_2276delCT variant in the PNPLA8 gene has been reported previously in an individual with a suspected mitochondrial myopathy, with progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis, who was compound heterozygous for the c.2275_2276delCT variant and another loss of function variant (Saunders et al., 2015). The c.2275_2276delCT variant causes a frameshift starting with codon Leucine 759, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu759AlafsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2275_2276delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2275_2276delCT as a variant of uncertain significance. - |
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