rs144226170
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_000302.4(PLOD1):c.776G>A(p.Arg259His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000302.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.776G>A | p.Arg259His | missense_variant | 8/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.917G>A | p.Arg306His | missense_variant | 9/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.776G>A | p.Arg259His | missense_variant | 8/19 | 1 | NM_000302.4 | P1 | |
PLOD1 | ENST00000429000.6 | c.782G>A | p.Arg261His | missense_variant | 8/8 | 5 | |||
PLOD1 | ENST00000465920.1 | n.726G>A | non_coding_transcript_exon_variant | 3/4 | 5 | ||||
PLOD1 | ENST00000485046.5 | n.819G>A | non_coding_transcript_exon_variant | 8/9 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000703 AC: 107AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251478Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135914
GnomAD4 exome AF: 0.0000978 AC: 143AN: 1461844Hom.: 0 Cov.: 31 AF XY: 0.0000839 AC XY: 61AN XY: 727232
GnomAD4 genome ? AF: 0.000703 AC: 107AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000713 AC XY: 53AN XY: 74306
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2023 | The p.R259H variant (also known as c.776G>A), located in coding exon 8 of the PLOD1 gene, results from a G to A substitution at nucleotide position 776. The arginine at codon 259 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
PLOD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2020 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 459826; Landrum et al., 2016) - |
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at