rs1555874538
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001379500.1(COL18A1):c.2833_2840del(p.Gly945ArgfsTer139) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G945G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00057 ( 0 hom., cov: 0)
Exomes 𝑓: 0.00043 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
COL18A1
NM_001379500.1 frameshift
NM_001379500.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.03
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]
SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 21-45504520-AGGCCCCCC-A is Pathogenic according to our data. Variant chr21-45504520-AGGCCCCCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438063.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL18A1 | NM_001379500.1 | c.2833_2840del | p.Gly945ArgfsTer139 | frameshift_variant | 34/42 | ENST00000651438.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL18A1 | ENST00000651438.1 | c.2833_2840del | p.Gly945ArgfsTer139 | frameshift_variant | 34/42 | NM_001379500.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000569 AC: 1AN: 1756Hom.: 0 Cov.: 0
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000429 AC: 7AN: 16314Hom.: 0 AF XY: 0.000394 AC XY: 3AN XY: 7608
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GnomAD4 genome ? AF: 0.000569 AC: 1AN: 1756Hom.: 0 Cov.: 0 AF XY: 0.00113 AC XY: 1AN XY: 888
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at