rs140929996
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_001166114.2(PNPLA6):c.1430C>T(p.Ser477Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. S477A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001166114.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNPLA6 | NM_001166114.2 | c.1430C>T | p.Ser477Leu | missense_variant | 12/32 | ENST00000600737.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNPLA6 | ENST00000600737.6 | c.1430C>T | p.Ser477Leu | missense_variant | 12/32 | 1 | NM_001166114.2 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000363 AC: 9AN: 248128Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135134
GnomAD4 exome AF: 0.0000685 AC: 100AN: 1460682Hom.: 0 Cov.: 35 AF XY: 0.0000784 AC XY: 57AN XY: 726646
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 39 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 438 of the PNPLA6 protein (p.Ser438Leu). This variant is present in population databases (rs140929996, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of PNPLA6-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 567501). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2023 | The c.1313C>T (p.S438L) alteration is located in exon 15 (coding exon 13) of the PNPLA6 gene. This alteration results from a C to T substitution at nucleotide position 1313, causing the serine (S) at amino acid position 438 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 16, 2021 | The inherited c.1430C>T (p.Ser477Leu) variant identified in the PNPLA6 gene substitutes a moderately conserved Serine for Leucine atamino acid 477/1366 (exon 12/32). This variant is found with low frequency in gnomAD(v3.1.1) (5 heterozygotes, 0 homozygotes; allele frequency: 3.29e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score: 0.219) and Benign (REVEL; score: 0.013) to the function of the canonical transcript. It is reported as a Variant of Uncertain Significance in ClinVar (VarID:567501) and to our current knowledge has not been reported in affected individuals in the literature. The p.Ser477 residue is not within a mapped domain of PNPLA6 (UniProtKB:Q8IY17). Given the lack of compelling evidence for its pathogenicity, the inherited c.1430C>T (p.Ser477Leu) variant identified in the PNPLA6 gene is reported as a Variant of Uncertain Significance. - |
Laurence-Moon syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 03-03-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at