3-33114550-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_006371.5(CRTAP):c.471+2C>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000822 in 1,580,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000084 ( 0 hom. )
Consequence
CRTAP
NM_006371.5 splice_donor, intron
NM_006371.5 splice_donor, intron
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 4.71
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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.44278607 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: aagGTaagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-33114550-C-T is Pathogenic according to our data. Variant chr3-33114550-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 847469.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRTAP | NM_006371.5 | c.471+2C>T | splice_donor_variant, intron_variant | ENST00000320954.11 | NP_006362.1 | |||
| CRTAP | NM_001393363.1 | c.471+2C>T | splice_donor_variant, intron_variant | NP_001380292.1 | ||||
| CRTAP | NM_001393364.1 | c.471+2C>T | splice_donor_variant, intron_variant | NP_001380293.1 | ||||
| CRTAP | NM_001393365.1 | c.471+2C>T | splice_donor_variant, intron_variant | NP_001380294.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 34
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GnomAD4 exome AF: 0.00000840 AC: 12AN: 1428398Hom.: 0 Cov.: 32 AF XY: 0.00000848 AC XY: 6AN XY: 707764
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GnomAD4 genome 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 7 Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change falls in intron 1 of the CRTAP gene. It does not directly change the encoded amino acid sequence of the CRTAP protein. It affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the c.471+2C nucleotide in the CRTAP gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18996919, 19550437). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
GERP RS
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