1-11934766-CCCATACCTCGG-C
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1PS1_ModeratePM2BS1_Supporting
The NM_000302.4(PLOD1):c.-9_2delACCTCGGCCAT(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,534,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
PLOD1
NM_000302.4 frameshift, start_lost
NM_000302.4 frameshift, start_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.687
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 Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 59 pathogenic variants in the truncated region.
PS1
Another start lost variant in NM_000302.4 (PLOD1) was described as [Pathogenic] in ClinVar as 3371745
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00031 (429/1382726) while in subpopulation NFE AF= 0.000376 (405/1076966). AF 95% confidence interval is 0.000346. There are 0 homozygotes in gnomad4_exome. There are 198 alleles in male gnomad4_exome subpopulation. 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PLOD1 | NM_000302.4 | c.-9_2delACCTCGGCCAT | p.Met1fs | frameshift_variant, start_lost | 1/19 | ENST00000196061.5 | NP_000293.2 | |
PLOD1 | NM_000302.4 | c.-9_2delACCTCGGCCAT | 5_prime_UTR_variant | 1/19 | ENST00000196061.5 | NP_000293.2 | ||
PLOD1 | NM_001316320.2 | c.-9_2delACCTCGGCCAT | p.Met1fs | frameshift_variant, start_lost | 1/20 | NP_001303249.1 | ||
PLOD1 | NM_001316320.2 | c.-9_2delACCTCGGCCAT | 5_prime_UTR_variant | 1/20 | NP_001303249.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLOD1 | ENST00000196061.5 | c.-9_2delACCTCGGCCAT | p.Met1fs | frameshift_variant, start_lost | 1/19 | 1 | NM_000302.4 | ENSP00000196061.4 | ||
PLOD1 | ENST00000196061 | c.-9_2delACCTCGGCCAT | 5_prime_UTR_variant | 1/19 | 1 | NM_000302.4 | ENSP00000196061.4 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152208Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.000310 AC: 429AN: 1382726Hom.: 0 AF XY: 0.000290 AC XY: 198AN XY: 682332
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PLOD1: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2024 | Has not been previously published as pathogenic or benign to our knowledge; Alters the Kozak sequence, which plays a major role in the initiation of translation - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 18, 2024 | Variant summary: PLOD1 c.-9_2del11 is a small deletion located in the 5' untranslated region and the first coding exon. It encompasses the first two nucleotides of the start codon. However, the remaining upstream nucleotides restore the sequence of the start codon, likely maintaining the original reading frame. This indicates the variant is less likely to be associated with disease, however functional studies have not been performed. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.-9_2del11 in individuals affected with Ehlers-Danlos Syndrome Type VI and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 422689). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2023 | The c.-9_2del11 variant (also known as p.M1?), located in the 5' untranslated region (5'UTR) and coding exon 1 of the PLOD1 gene, results from a deletion of 11 nucleotides between positions -9 and 2. This deletion interrupts the native ATG initiation codon; however, the remaining realigned nucleotides recreate an ATG initiation codon at the same position and is predicted to maintain the normal reading frame. However, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 04, 2022 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at