Variant 3-33114093-CGGGGGGCCGCGGCGCT-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006371.5(CRTAP):c.18_33del(p.Gly7Ter) 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 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: 0.0000084 ( 0 hom. )

Consequence

CRTAP
NM_006371.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.06

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:

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ACMG classification

Classification made for transcript

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-CGGGGGGCCGCGGCGCT-C is Pathogenic according to our data. Variant chr3-33114093-CGGGGGGCCGCGGCGCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1070167.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CRTAP	NM_006371.5 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/6
CRTAP	NM_001393364.1 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/6
CRTAP	NM_001393365.1 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1 linkuse as main transcript	c.18_33del	p.Gly7Ter	frameshift_variant	1/6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000109

AC:

AN:

73368

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

42892

show subpopulations

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:

AN:

1310866

Hom.:

AF XY:

0.00000464

AC XY:

AN XY:

647122

show subpopulations

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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