rs778909108
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001379500.1(COL18A1):βc.1593delβ(p.Pro534LeufsTer190) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
COL18A1
NM_001379500.1 frameshift
NM_001379500.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.61
Genes affected
COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 21-45480834-TC-T is Pathogenic according to our data. Variant chr21-45480834-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL18A1 | NM_001379500.1 | c.1593del | p.Pro534LeufsTer190 | frameshift_variant | 13/42 | ENST00000651438.1 | |
COL18A1 | NM_130444.3 | c.2838del | p.Pro949LeufsTer190 | frameshift_variant | 12/41 | ||
COL18A1 | NM_030582.4 | c.2133del | p.Pro714LeufsTer190 | frameshift_variant | 12/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL18A1 | ENST00000651438.1 | c.1593del | p.Pro534LeufsTer190 | frameshift_variant | 13/42 | NM_001379500.1 | |||
COL18A1 | ENST00000355480.10 | c.2133del | p.Pro714LeufsTer190 | frameshift_variant | 12/41 | 1 | |||
COL18A1 | ENST00000359759.8 | c.2838del | p.Pro949LeufsTer190 | frameshift_variant | 12/41 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458942Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2AN XY: 725788
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35
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2
AN XY:
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 447114). This variant has not been reported in the literature in individuals affected with COL18A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro534Leufs*190) in the COL18A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL18A1 are known to be pathogenic (PMID: 12415512, 25456301). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 22, 2016 | - - |
Computational scores
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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