rs145999340
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting
The NM_020376.4(PNPLA2):c.338G>A(p.Arg113His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020376.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA2 | NM_020376.4 | c.338G>A | p.Arg113His | missense_variant | 3/10 | ENST00000336615.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA2 | ENST00000336615.9 | c.338G>A | p.Arg113His | missense_variant | 3/10 | 1 | NM_020376.4 | P1 | |
PNPLA2 | ENST00000525250.5 | n.944G>A | non_coding_transcript_exon_variant | 1/6 | 2 | ||||
PNPLA2 | ENST00000534561.1 | n.5G>A | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000322 AC: 81AN: 251282Hom.: 0 AF XY: 0.000368 AC XY: 50AN XY: 135882
GnomAD4 exome AF: 0.000205 AC: 299AN: 1461632Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 167AN XY: 727106
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74488
ClinVar
Submissions by phenotype
Neutral lipid storage myopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 26, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 113 of the PNPLA2 protein (p.Arg113His). This variant is present in population databases (rs145999340, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with PNPLA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 465792). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNPLA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PNPLA2 function (PMID: 21170305). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at