3-33114090-CGCCGGGGG-C

Variant names:

• chr3-33114090-CGCCGGGGG-C
• NM_006371.5:c.18_25delGGGGGCCG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006371.5(CRTAP):​c.18_25delGGGGGCCG​(p.Ala10SerfsTer148) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000306 in 1,309,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.06

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 Likely_pathogenic. Variant got 8 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114090-CGCCGGGGG-C is Pathogenic according to our data. Variant chr3-33114090-CGCCGGGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2633856.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.18_25delGGGGGCCG	p.Ala10SerfsTer148	frameshift_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.18_25delGGGGGCCG	p.Ala10SerfsTer148	frameshift_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.18_25delGGGGGCCG	p.Ala10SerfsTer148	frameshift_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.18_25delGGGGGCCG	p.Ala10SerfsTer158	frameshift_variant	Exon 1 of 6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.18_25delGGGGGCCG	p.Ala10SerfsTer148	frameshift_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.18_25delGGGGGCCG	p.Ala10SerfsTer148	frameshift_variant	Exon 1 of 6	2		ENSP00000409997.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000306 AC: 4 AN: 1309076 Hom.: 0 AF XY: 0.00000619 AC XY: 4 AN XY: 646254

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000383

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:1

Nov 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala10Serfs*148) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of CRTAP-related conditions (PMID: 18566967, 34627339). For these reasons, this variant has been classified as Pathogenic. -

CRTAP-related disorder Pathogenic:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CRTAP c.18_25del8 variant is predicted to result in a frameshift and premature protein termination (p.Ala10Serfs*148). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift variants in CRTAP are expected to be pathogenic and have been documented near this variant (Baldridge et al. 2008. PubMed ID: 18566967; Li et al. 2020. PubMed ID: 33093841). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33155582;