rs140758113
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The NM_000302.4(PLOD1):c.804C>T(p.Thr268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00088 in 1,613,984 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00091 ( 0 hom. )
Consequence
PLOD1
NM_000302.4 synonymous
NM_000302.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -6.73
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 Benign. Variant got -8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
Variant 1-11957904-C-T is Benign according to our data. Variant chr1-11957904-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264284.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr1-11957904-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-6.73 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000617 (94/152284) while in subpopulation NFE AF= 0.00113 (77/68020). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.804C>T | p.Thr268= | synonymous_variant | 8/19 | ENST00000196061.5 | |
PLOD1 | NM_001316320.2 | c.945C>T | p.Thr315= | synonymous_variant | 9/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.804C>T | p.Thr268= | synonymous_variant | 8/19 | 1 | NM_000302.4 | P1 | |
PLOD1 | ENST00000429000.6 | c.810C>T | p.Thr270= | synonymous_variant | 8/8 | 5 | |||
PLOD1 | ENST00000465920.1 | n.754C>T | non_coding_transcript_exon_variant | 3/4 | 5 | ||||
PLOD1 | ENST00000485046.5 | n.847C>T | non_coding_transcript_exon_variant | 8/9 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000618 AC: 94AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000608 AC: 153AN: 251440Hom.: 0 AF XY: 0.000655 AC XY: 89AN XY: 135896
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GnomAD4 exome AF: 0.000908 AC: 1327AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000895 AC XY: 651AN XY: 727172
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GnomAD4 genome ? AF: 0.000617 AC: 94AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | PLOD1: BP4, BP7 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2021 | - - |
PLOD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 13, 2019 | 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). - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2015 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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