rs72659357

Positions:

• chr3-33114080-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006371.5(CRTAP):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRTAP NM_006371.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.833

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114080-G-A is Pathogenic according to our data. Variant chr3-33114080-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.3G>A	p.Met1?	start_lost	1/7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.3G>A	p.Met1?	start_lost	1/6		NP_001380292.1
CRTAP	NM_001393364.1	c.3G>A	p.Met1?	start_lost	1/6		NP_001380293.1
CRTAP	NM_001393365.1	c.3G>A	p.Met1?	start_lost	1/6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.3G>A	p.Met1?	start_lost	1/7	1	NM_006371.5	ENSP00000323696	P1
CRTAP	ENST00000449224.1	c.3G>A	p.Met1?	start_lost	1/6	2		ENSP00000409997

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000230 AC: 3 AN: 1306822 Hom.: 0 Cov.: 31 AF XY: 0.00000310 AC XY: 2 AN XY: 645182

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000287

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 28, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2023	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 CRTAP-related 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. ClinVar contains an entry for this variant (Variation ID: 4951). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 04, 2022

Variant summary: CRTAP c.3G>A (p.Met1?, aka p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The first potential downstream in-frame start codon (ATG) is located in exon 1 at Met42. Several truncations have been reported 5' of Met42 in the CRTAP gene in affected individuals (HGMD). The variant was absent in 72958 control chromosomes (gnomAD). The variant, c.3G>A, has been reported in the literature in an infant affected with Osteogenesis Imperfecta, who carried a frameshift variant in trans (Barnes_2006). Authors of this study also analyzed patient derived cells, and reported that the father of the infant, whose variant alters the start codon, produced both normal and a smaller size CRTAP protein, suggesting that his cells contain a truncated form of CRTAP (likely initiated at the next methionine codon, Met42), and although they could not detect the truncated form in the infant, collagen prolyl 3-hydroxylation measurements suggested that the infant had some residual enzyme activity, supposedly derived from the paternal allele (Barnes_2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	A;A
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.39	B;B
Vest4		0.84
MutPred		0.59		Loss of glycosylation at P3 (P = 0.0312);Loss of glycosylation at P3 (P = 0.0312);
MVP		0.66
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.92
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs72659357; hg19: chr3-33155572;