3-33114079-T-C

Variant names:

• chr3-33114079-T-C
• NM_006371.5:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_006371.5(CRTAP):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,306,852 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CRTAP NM_006371.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 42 codons. Genomic position: 33114201. Lost 0.103 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114079-T-C is Pathogenic according to our data. Variant chr3-33114079-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2914570.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	2		ENSP00000409997.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000689 AC: 9 AN: 1306852 Hom.: 0 Cov.: 31 AF XY: 0.00000620 AC XY: 4 AN XY: 645244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000283

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000670

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:1

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CRTAP mRNA. The next in-frame methionine is located at codon 42. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with osteogenesis imperfecta (PMID: 17192541). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.82	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.60	P;P
Vest4		0.90
MutPred		0.58		Loss of glycosylation at P3 (P = 0.0312);Loss of glycosylation at P3 (P = 0.0312);
MVP		0.64
ClinPred		0.91	D
GERP RS		3.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.91
gMVP		0.78

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33155571;