NM_006371.5:c.118_133delGAGCTGATGCCGCTCGinsTACCC

Variant names:

• chr3-33114195-GAGCTGATGCCGCTCG-TACCC
• rs387907333
• NM_006371.5:c.118_133delGAGCTGATGCCGCTCGinsTACCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_006371.5(CRTAP):​c.118_133delGAGCTGATGCCGCTCGinsTACCC​(p.Glu40TyrfsTer117) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CRTAP NM_006371.5 frameshift, missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.38
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 7

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-33114195-GAGCTGATGCCGCTCG-TACCC is Pathogenic according to our data. Variant chr3-33114195-GAGCTGATGCCGCTCG-TACCC is described in ClinVar as Pathogenic. ClinVar VariationId is 41922.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006371.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	NM_006371.5	MANE Select	c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 6	NP_001380293.1	C9JP16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.118_133delGAGCTGATGCCGCTCGinsTACCC	p.Glu40TyrfsTer117	frameshift missense	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907333; hg19: chr3-33155687;