rs137853943

Variant names:

Your query was ambiguous. Multiple possible variants found:

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

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CRTAP
NM_006371.5 splice_donor, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.71

Variant links:

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]

CRTAP links:

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	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5 link	c.471+2C>A	splice_donor_variant, intron_variant	Intron 1 of 6	ENST00000320954.11	NP_006362.1	O75718
CRTAP	NM_001393363.1 link	c.471+2C>A	splice_donor_variant, intron_variant	Intron 1 of 5		NP_001380292.1
CRTAP	NM_001393364.1 link	c.471+2C>A	splice_donor_variant, intron_variant	Intron 1 of 5		NP_001380293.1
CRTAP	NM_001393365.1 link	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 link	c.471+2C>A		splice_donor_variant, intron_variant	Intron 1 of 6	1	NM_006371.5	ENSP00000323696.5		O75718
CRTAP	ENST00000449224.1 link	c.471+2C>A		splice_donor_variant, intron_variant	Intron 1 of 5	2		ENSP00000409997.1		C9JP16

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000823

AC:

AN:

182178

Hom.:

AF XY:

0.0000998

AC XY:

AN XY:

100212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000171

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000391

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.000170

AC:

243

AN:

1428398

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

123

AN XY:

707764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000365

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000204

Gnomad4 OTH exome

AF:

0.000136

GnomAD4 genome

AF:

0.000125

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000448

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Pathogenic:6

Apr 08, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting -

Dec 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta

Pathogenic:2

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 26, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19550437, 21239989, 31980526, 31589614, 18996919) -

CRTAP-related disorder

Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Benign

0.89

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

GERP RS

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.86

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over