rs137853943
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000320954.11(CRTAP):c.471+2C>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000166 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
CRTAP
ENST00000320954.11 splice_donor
ENST00000320954.11 splice_donor
Scores
2
2
3
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-33114550-C-A is Pathogenic according to our data. Variant chr3-33114550-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRTAP | NM_006371.5 | c.471+2C>A | splice_donor_variant | ENST00000320954.11 | NP_006362.1 | |||
| CRTAP | NM_001393363.1 | c.471+2C>A | splice_donor_variant | NP_001380292.1 | ||||
| CRTAP | NM_001393364.1 | c.471+2C>A | splice_donor_variant | NP_001380293.1 | ||||
| CRTAP | NM_001393365.1 | c.471+2C>A | splice_donor_variant | NP_001380294.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CRTAP | ENST00000320954.11 | c.471+2C>A | splice_donor_variant | 1 | NM_006371.5 | ENSP00000323696 | P1 | |||
| CRTAP | ENST00000449224.1 | c.471+2C>A | splice_donor_variant | 2 | ENSP00000409997 |
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152208Hom.: 0 Cov.: 34
GnomAD3 genomes
AF:
AC:
19
AN:
152208
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000823 AC: 15AN: 182178Hom.: 0 AF XY: 0.0000998 AC XY: 10AN XY: 100212
GnomAD3 exomes
AF:
AC:
15
AN:
182178
Hom.:
AF XY:
AC XY:
10
AN XY:
100212
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000170 AC: 243AN: 1428398Hom.: 0 Cov.: 32 AF XY: 0.000174 AC XY: 123AN XY: 707764
GnomAD4 exome
AF:
AC:
243
AN:
1428398
Hom.:
Cov.:
32
AF XY:
AC XY:
123
AN XY:
707764
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000125 AC: 19AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7AN XY: 74356
GnomAD4 genome
AF:
AC:
19
AN:
152208
Hom.:
Cov.:
34
AF XY:
AC XY:
7
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
5
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 7 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 02, 2014 | The c.471+2C>A variant in CRTAP has been reported in 2 homozygous and 1 compound heterozygous individuals with Osteogenesis imperfecta type II (Bodian 2009, Van Dijk 2009) and was found to segregate with disease in 2 affected family members (Van Dijk 2009). Data from large population studies is insufficient to assess the frequency of this variant. This variant occurs in the +/- 1/2 region of the splice sequence and functional studies indicate this variant leads to aberrant splicing (Van Dijk 2009). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact to the protein, segregation studies, and functional evidence. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 12, 2018 | The CRTAP c.471+2C>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.471+2C>A variant has been reported two studies and is found in a total of five individuals with osteogenesis imperfecta, including in two in a homozygous state, and in three in a compound heterozygous state from the same family (Bodian et al. 2009; Van Dijk et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.0002 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of splice donor variants, the c.471+2C>A variant is classified as likely pathogenic for osteogenesis imperfect. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 17, 2021 | The CRTAP c.471+2C>A variant (rs137853943) has been published in the homozygous and compound heterozygous state in individuals with osteogenesis imperfecta (Bodian 2009, Van Dijk 2009). The variant is reported as pathogenic or likely pathogenic in the ClinVar database (Variation ID: 208570) and is listed in the general population with an overall allele frequency of 0.008% (18/213,550 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function and one functional study supports this prediction (Van Dijk 2009). Based on available information, this variant is classified as pathogenic. References: Bodian DL et al. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Genet. 2009 Feb 1;18(3):463-71. Van Dijk FS et al. CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis. Eur J Hum Genet. 2009 Dec;17(12):1560-9. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 08, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change affects a donor splice site in intron 1 of the CRTAP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CRTAP are known to be pathogenic (PMID: 17055431, 19862557, 24715559). This variant is present in population databases (rs137853943, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 18996919, 19550437). ClinVar contains an entry for this variant (Variation ID: 208570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Osteogenesis imperfecta Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2024 | Variant summary: CRTAP c.471+2C>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CRTAP function. The variant allele was found at a frequency of 8.2e-05 in 182178 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CRTAP causing Osteogenesis Imperfecta (8.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.471+2C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Osteogenesis Imperfecta (Bodian_2009, Van Dijk_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18996919, 19550437). ClinVar contains an entry for this variant (Variation ID: 208570). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2019 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2021 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18996919, 19550437, 21239989, 31980526, 31589614) - |
CRTAP-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2023 | The CRTAP c.471+2C>A variant is predicted to interfere with splicing. This variant was reported in the homozygous state in a patient with osteogenesis imperfecta, who was born to non-consanguineous parents (Bodian et al. 2009. PubMed ID: 18996919). This variant was also reported in the compound heterozygous state in another patient with osteogenesis imperfecta, and RNA study suggested this variant affected splicing (Van Dijk et al. 2009. PubMed ID: 19550437)This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at