rs147940796
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP3BP4_ModerateBS1_Supporting
The NM_000302.4(PLOD1):c.785C>T(p.Thr262Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
PLOD1
NM_000302.4 missense
NM_000302.4 missense
Scores
7
8
3
Clinical Significance
Conservation
PhyloP100: 7.81
Genes affected
PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.26133478).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000499 (76/152176) while in subpopulation AFR AF= 0.00176 (73/41434). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.785C>T | p.Thr262Ile | missense_variant | 8/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.926C>T | p.Thr309Ile | missense_variant | 9/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.785C>T | p.Thr262Ile | missense_variant | 8/19 | 1 | NM_000302.4 | P1 | |
PLOD1 | ENST00000429000.6 | c.791C>T | p.Thr264Ile | missense_variant | 8/8 | 5 | |||
PLOD1 | ENST00000465920.1 | n.735C>T | non_coding_transcript_exon_variant | 3/4 | 5 | ||||
PLOD1 | ENST00000485046.5 | n.828C>T | non_coding_transcript_exon_variant | 8/9 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000499 AC: 76AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000139 AC: 35AN: 251476Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135914
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461842Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727240
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GnomAD4 genome ? AF: 0.000499 AC: 76AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 262 of the PLOD1 protein (p.Thr262Ile). This variant is present in population databases (rs147940796, gnomAD 0.2%). 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: 459828). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 24, 2018 | The PLOD1 c.785C>T; p.Thr262Ile variant (rs147940796), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 459828). This variant is found in the African population with an overall allele frequency of 0.15% (37/24018 alleles) in the Genome Aggregation Database. The threonine at codon 262 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Thr262Ile variant is uncertain at this time. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2023 | The p.T262I variant (also known as c.785C>T), located in coding exon 8 of the PLOD1 gene, results from a C to T substitution at nucleotide position 785. The threonine at codon 262 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#459828; Landrum et al., 2016) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.98
.;D
Vest4
0.97
MVP
MPC
0.69
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at