3-33114090-C-CGCCGGGGG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006371.5(CRTAP):c.18_25dupGGGGGCCG(p.Ala9GlyfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CRTAP
NM_006371.5 frameshift
NM_006371.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.20
Genes affected
CRTAP (HGNC:2379): (cartilage associated protein) The protein encoded by this gene is similar to the chicken and mouse CRTAP genes. The encoded protein is a scaffolding protein that may influence the activity of at least one member of the cytohesin/ARNO family in response to specific cellular stimuli. Defects in this gene are associated with osteogenesis imperfecta, a connective tissue disorder characterized by bone fragility and low bone mass. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 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 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-33114090-C-CGCCGGGGG is Pathogenic according to our data. Variant chr3-33114090-C-CGCCGGGGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2725831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CRTAP | NM_006371.5 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 7 | ENST00000320954.11 | NP_006362.1 | |
CRTAP | NM_001393363.1 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 6 | NP_001380292.1 | ||
CRTAP | NM_001393364.1 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 6 | NP_001380293.1 | ||
CRTAP | NM_001393365.1 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 6 | NP_001380294.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRTAP | ENST00000320954.11 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 7 | 1 | NM_006371.5 | ENSP00000323696.5 | ||
CRTAP | ENST00000449224.1 | c.18_25dupGGGGGCCG | p.Ala9GlyfsTer7 | frameshift_variant | Exon 1 of 6 | 2 | ENSP00000409997.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 34
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1309074Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 646252
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 7 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 11, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Ala9Glyfs*7) in the CRTAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRTAP are known to be pathogenic (PMID: 17055431, 19862557, 24715559). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive osteogenesis imperfecta (PMID: 33093841). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at