3-33114093-CGGGGGGCCGCGGCGCT-C

Variant names:

• chr3-33114093-CGGGGGGCCGCGGCGCT-C
• rs752412772
• NM_006371.5:c.18_33delGGGGGCCGCGGCGCTG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006371.5(CRTAP):​c.18_33delGGGGGCCGCGGCGCTG​(p.Gly7fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,310,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 14 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 3-33114093-CGGGGGGCCGCGGCGCT-C is Pathogenic according to our data. Variant chr3-33114093-CGGGGGGCCGCGGCGCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1070167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.18_33delGGGGGCCGCGGCGCTG	p.Gly7fs	frameshift_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.18_33delGGGGGCCGCGGCGCTG	p.Gly7fs	frameshift_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.18_33delGGGGGCCGCGGCGCTG	p.Gly7fs	frameshift_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.18_33delGGGGGCCGCGGCGCTG	p.Gly7fs	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_33delGGGGGCCGCGGCGCTG	p.Gly7fs	frameshift_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.18_33delGGGGGCCGCGGCGCTG	p.Gly7fs	frameshift_variant	Exon 1 of 6	2		ENSP00000409997.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.000109 AC: 8 AN: 73368 Hom.: 0 AF XY: 0.0000233 AC XY: 1 AN XY: 42892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000839 AC: 11 AN: 1310866 Hom.: 0 AF XY: 0.00000464 AC XY: 3 AN XY: 647122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000468

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:2

Jul 23, 2024

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.Gly7*) 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 present in population databases (rs752412772, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1070167). For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 07, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19862557, 17055431, 24715559) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752412772; hg19: chr3-33155585;