3-33114093-CG-CGG

Variant names:

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

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.22dupG​(p.Ala8GlyfsTer153) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,310,854 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. A8A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CRTAP NM_006371.5 frameshift
• Clinical Significance: 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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-C-CG is Pathogenic according to our data. Variant chr3-33114093-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 1324173.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.22dupG	p.Ala8GlyfsTer153	frameshift_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.22dupG	p.Ala8GlyfsTer153	frameshift_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.22dupG	p.Ala8GlyfsTer153	frameshift_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.22dupG	p.Ala8GlyfsTer163	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.22dupG	p.Ala8GlyfsTer153	frameshift_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.22dupG	p.Ala8GlyfsTer153	frameshift_variant	Exon 1 of 6	2		ENSP00000409997.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000687 AC: 9 AN: 1310854 Hom.: 0 Cov.: 31 AF XY: 0.00000773 AC XY: 5 AN XY: 647114

African (AFR) AF: 0.00 AC: 0 AN: 26266

American (AMR) AF: 0.00 AC: 0 AN: 23512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22588

East Asian (EAS) AF: 0.00 AC: 0 AN: 28830

South Asian (SAS) AF: 0.0000563 AC: 4 AN: 70986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32970

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

European-Non Finnish (NFE) AF: 0.00000382 AC: 4 AN: 1046882

Other (OTH) AF: 0.0000184 AC: 1 AN: 54250

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:2

May 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1324173). This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta (PMID: 35186396). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala8Glyfs*153) 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). -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;