3-33114093-CG-CGGG

Variant names:

• chr3-33114093-C-CGG
• rs137853936
• NM_006371.5:c.21_22dupGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006371.5(CRTAP):​c.21_22dupGG​(p.Ala8GlyfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.118
• Publications: 3 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: Pathogenic. The variant received 11 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 53 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114093-C-CGG is Pathogenic according to our data. Variant chr3-33114093-C-CGG is described in ClinVar as Pathogenic. ClinVar VariationId is 1175017.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.21_22dupGG	p.Ala8GlyfsTer6	frameshift	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.21_22dupGG	p.Ala8GlyfsTer6	frameshift	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.21_22dupGG	p.Ala8GlyfsTer6	frameshift	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.21_22dupGG	p.Ala8GlyfsTer6	frameshift	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.21_22dupGG	p.Ala8GlyfsTer6	frameshift	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.21_22dupGG	p.Ala8GlyfsTer6	frameshift	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs137853936; hg19: chr3-33155585;