rs786205882
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001256007.3(PNPLA8):c.634_637del(p.Asn212HisfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,610,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PNPLA8
NM_001256007.3 frameshift
NM_001256007.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.68
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-108514854-GAATT-G is Pathogenic according to our data. Variant chr7-108514854-GAATT-G is described in ClinVar as [Pathogenic]. Clinvar id is 190127.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-108514854-GAATT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA8 | NM_001256007.3 | c.634_637del | p.Asn212HisfsTer29 | frameshift_variant | 3/11 | ENST00000257694.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA8 | ENST00000257694.13 | c.634_637del | p.Asn212HisfsTer29 | frameshift_variant | 3/11 | 1 | NM_001256007.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457976Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 725616
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Mitochondrial myopathy-lactic acidosis-deafness syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | This sequence change creates a premature translational stop signal (p.Asn212Hisfs*29) in the PNPLA8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNPLA8 are known to be pathogenic (PMID: 29681094). 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 mitochondrial myopathy with lactic acidosis (PMID: 25512002). This variant is also known as c.334_337delAATT (p.Asn112HisfsX29). ClinVar contains an entry for this variant (Variation ID: 190127). For these reasons, this variant has been classified as Pathogenic. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at