3-33114093-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006371.5(CRTAP):c.22del(p.Ala8ProfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,310,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.118

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114093-CG-C is Pathogenic according to our data. Variant chr3-33114093-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2161328.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/6
CRTAP	NM_001393364.1	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/6
CRTAP	NM_001393365.1	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.22del	p.Ala8ProfsTer5	frameshift_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000168 AC: 22 AN: 1310770 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 8 AN XY: 647072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000694

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000369

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

This sequence change creates a premature translational stop signal (p.Ala8Profs*5) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta (PMID: 35186396). ClinVar contains an entry for this variant (Variation ID: 2161328). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs137853936; hg19: chr3-33155585;