6-36270574-GC-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001374623.1(PNPLA1):c.121delC(p.Arg41fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000451 in 1,551,620 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000036 ( 0 hom. )
Consequence
PNPLA1
NM_001374623.1 frameshift
NM_001374623.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.41
Genes affected
PNPLA1 (HGNC:21246): (patatin like phospholipase domain containing 1) The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]
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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
Very rare variant in population databases, with high coverage;
PP5
Variant 6-36270574-GC-G is Pathogenic according to our data. Variant chr6-36270574-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3391281.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PNPLA1 | NM_001374623.1 | c.121delC | p.Arg41fs | frameshift_variant | 1/9 | ENST00000636260.2 | NP_001361552.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PNPLA1 | ENST00000636260.2 | c.121delC | p.Arg41fs | frameshift_variant | 1/9 | 5 | NM_001374623.1 | ENSP00000490785.2 | ||
| PNPLA1 | ENST00000457797.5 | c.121delC | p.Arg41fs | frameshift_variant | 1/8 | 1 | ENSP00000391868.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000649 AC: 1AN: 154112Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81904
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GnomAD4 exome AF: 0.00000357 AC: 5AN: 1399256Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3AN XY: 690134
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GnomAD4 genome 0.0000131 AC: 2AN: 152364Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74500
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 10 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | The observed frameshift c.121delp.Arg41GlyfsTer17 variant in PNPLA1 gene has been reported previously in compound heterozygous state in individuals affected with congenital ichthyosis Zimmer AD, et al., 2017. The p.Arg41GlyfsTer17 variant is present with allele frequency of 0.0006% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. This variant causes a frameshift starting with codon Arginine 41, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Arg41GlyfsTer17. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another reportable variant in PNPLA1 gene, the molecular diagnosis is not confirmed. - |
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