chr6-36291532-T-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001374623.1(PNPLA1):c.418T>C(p.Ser140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,325,798 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001374623.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PNPLA1 | NM_001374623.1 | c.418T>C | p.Ser140Pro | missense_variant | Exon 2 of 9 | ENST00000636260.2 | NP_001361552.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNPLA1 | ENST00000636260.2 | c.418T>C | p.Ser140Pro | missense_variant | Exon 2 of 9 | 5 | NM_001374623.1 | ENSP00000490785.2 | ||
PNPLA1 | ENST00000457797.5 | c.418T>C | p.Ser140Pro | missense_variant | Exon 2 of 8 | 1 | ENSP00000391868.1 |
Frequencies
GnomAD3 genomes AF: 0.0000254 AC: 3AN: 117946Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.00000824 AC: 2AN: 242832Hom.: 0 AF XY: 0.00000763 AC XY: 1AN XY: 131138
GnomAD4 exome AF: 0.0000166 AC: 20AN: 1207852Hom.: 0 Cov.: 33 AF XY: 0.0000117 AC XY: 7AN XY: 597248
GnomAD4 genome AF: 0.0000254 AC: 3AN: 117946Hom.: 0 Cov.: 29 AF XY: 0.0000185 AC XY: 1AN XY: 54026
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 10 Pathogenic:3
This variant has been seen as a compound heterozygote in 2 differents families in association with the variant c.[820_820delC],[p.Arg274Glyfs*7]; or with the variant c.[266C>T], [p.Pro89Leu]. -
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Lamellar ichthyosis Pathogenic:1
Variant summary: PNPLA1 c.418T>C (p.Ser140Pro) results in a non-conservative amino acid change located in the patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 242832 control chromosomes. c.418T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Lamellar Ichthyosis and has been found to segregate with disease in at least one family (e.g. Pichery_2017, Zimmer_2017, Boyden_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28403545, 28369476, 28093717). ClinVar contains an entry for this variant (Variation ID: 375256). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31120544, 35893253, 28369476) -
Congenital ichthyosiform erythroderma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at