rs576907642
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_000302.4(PLOD1):āc.1427A>Gā(p.Lys476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. K476K) has been classified as Likely benign.
Frequency
Consequence
NM_000302.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.1427A>G | p.Lys476Arg | missense_variant | 13/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.1568A>G | p.Lys523Arg | missense_variant | 14/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.1427A>G | p.Lys476Arg | missense_variant | 13/19 | 1 | NM_000302.4 | P1 | |
PLOD1 | ENST00000470133.1 | n.41A>G | non_coding_transcript_exon_variant | 1/3 | 3 | ||||
PLOD1 | ENST00000491536.5 | n.55A>G | non_coding_transcript_exon_variant | 1/5 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152256Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251264Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135884
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461392Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 726998
GnomAD4 genome AF: 0.000243 AC: 37AN: 152374Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18AN XY: 74508
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 13, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 476 of the PLOD1 protein (p.Lys476Arg). This variant is present in population databases (rs576907642, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498773). 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 arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 24, 2023 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2021 | The p.K476R variant (also known as c.1427A>G), located in coding exon 13 of the PLOD1 gene, results from an A to G substitution at nucleotide position 1427. The lysine at codon 476 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other 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. - |
Ehlers-Danlos syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2019 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at