Variant chr3-33114079-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.88

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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/exons	MANE	Protein
CRTAP	NM_006371.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/6		NP_001380292.1
CRTAP	NM_001393364.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/6		NP_001380293.1
CRTAP	NM_001393365.1 linkuse as main transcript	c.2T>C	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 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/7	1	NM_006371.5	ENSP00000323696	P1
CRTAP	ENST00000449224.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/6	2		ENSP00000409997

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000689

AC:

AN:

1306852

Hom.:

Cov.:

AF XY:

0.00000620

AC XY:

AN XY:

645244

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 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 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

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Benign

-0.82

MutationTaster

Benign

1.0

D;D

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over