3-33114521-C-G

Variant names:

• chr3-33114521-C-G
• rs972668240
• NM_006371.5:c.444C>G

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.444C>G​(p.Tyr148*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000689 in 1,451,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y148Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CRTAP NM_006371.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.74
• Publications: 0 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-33114521-C-G is Pathogenic according to our data. Variant chr3-33114521-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 465810.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.444C>G	p.Tyr148*	stop_gained	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.444C>G	p.Tyr148*	stop_gained	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.444C>G	p.Tyr148*	stop_gained	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.444C>G	p.Tyr148*	stop_gained	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.444C>G	p.Tyr148*	stop_gained	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.444C>G	p.Tyr148*	stop_gained	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 218710 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000689 AC: 10 AN: 1451286 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 721188

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4324

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108858

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.7
Vest4		0.75
GERP RS		2.5
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs972668240; hg19: chr3-33156013;