rs972668240

Positions:

• chr3-33114521-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006371.5(CRTAP):​c.444C>G​(p.Tyr148Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000689 in 1,451,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y148Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CRTAP NM_006371.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114521-C-G is Pathogenic according to our data. Variant chr3-33114521-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 465810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.444C>G	p.Tyr148Ter	stop_gained	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.444C>G	p.Tyr148Ter	stop_gained	1/6
CRTAP	NM_001393364.1	c.444C>G	p.Tyr148Ter	stop_gained	1/6
CRTAP	NM_001393365.1	c.444C>G	p.Tyr148Ter	stop_gained	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.444C>G	p.Tyr148Ter	stop_gained	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.444C>G	p.Tyr148Ter	stop_gained	1/6	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451286 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained variant c.444C>G (p.Tyr148Ter) in CRTAP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr148Ter variant is novel (not in any individuals) in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.444C>G in CRTAP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 465810). This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr148*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A
Vest4		0.75
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs972668240; hg19: chr3-33156013;