chr3-33114093-CG-C

Variant names:

• chr3-33114093-CG-C
• rs137853936
• NM_006371.5:c.22delG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006371.5(CRTAP):​c.22delG​(p.Ala8ProfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,310,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts 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 16 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.
• PP5: Variant 3-33114093-CG-C is Pathogenic according to our data. Variant chr3-33114093-CG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2161328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.22delG	p.Ala8ProfsTer5	frameshift	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.22delG	p.Ala8ProfsTer5	frameshift	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.22delG	p.Ala8ProfsTer5	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.22delG	p.Ala8ProfsTer5	frameshift	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.22delG	p.Ala8ProfsTer5	frameshift	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.22delG	p.Ala8ProfsTer5	frameshift	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000273 AC: 2 AN: 73368 AF XY: 0.0000233

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000168 AC: 22 AN: 1310770 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 8 AN XY: 647072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26262

American (AMR) AF: 0.0000851 AC: 2 AN: 23502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22582

East Asian (EAS) AF: 0.0000694 AC: 2 AN: 28830

South Asian (SAS) AF: 0.00 AC: 0 AN: 70974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4570

European-Non Finnish (NFE) AF: 0.0000153 AC: 16 AN: 1046840

Other (OTH) AF: 0.0000369 AC: 2 AN: 54250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000728655), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Osteogenesis imperfecta type 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137853936; hg19: chr3-33155585; COSMIC: COSV58013067; COSMIC: COSV58013067;