rs137853943
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006371.5(CRTAP):c.471+2C>A variant causes a splice donor, intron 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
Consequence
NM_006371.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CRTAP | NM_006371.5 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 6 | ENST00000320954.11 | NP_006362.1 | ||
CRTAP | NM_001393363.1 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 5 | NP_001380292.1 | |||
CRTAP | NM_001393364.1 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 5 | NP_001380293.1 | |||
CRTAP | NM_001393365.1 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 5 | NP_001380294.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRTAP | ENST00000320954.11 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 6 | 1 | NM_006371.5 | ENSP00000323696.5 | |||
CRTAP | ENST00000449224.1 | c.471+2C>A | splice_donor_variant, intron_variant | Intron 1 of 5 | 2 | ENSP00000409997.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152208Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000823 AC: 15AN: 182178Hom.: 0 AF XY: 0.0000998 AC XY: 10AN XY: 100212
GnomAD4 exome AF: 0.000170 AC: 243AN: 1428398Hom.: 0 Cov.: 32 AF XY: 0.000174 AC XY: 123AN XY: 707764
GnomAD4 genome AF: 0.000125 AC: 19AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7AN XY: 74356
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type 7 Pathogenic:6
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. -
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. -
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. -
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. -
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting -
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Osteogenesis imperfecta Pathogenic:2
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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. -
not provided Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at