chr3-33114085-C-A

Position:

• chr3-33114085-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006371.5(CRTAP):​c.8C>A​(p.Pro3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P3P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.338

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10321522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.8C>A	p.Pro3Gln	missense_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.8C>A	p.Pro3Gln	missense_variant	1/6
CRTAP	NM_001393364.1	c.8C>A	p.Pro3Gln	missense_variant	1/6
CRTAP	NM_001393365.1	c.8C>A	p.Pro3Gln	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.8C>A	p.Pro3Gln	missense_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.8C>A	p.Pro3Gln	missense_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1308434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 645960

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152026 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74266

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2022

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 3 of the CRTAP protein (p.Pro3Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.47	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.95	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.043
Sift	Benign	0.099	T;T
Sift4G	Uncertain	0.059	T;D
Polyphen		0.016	B;B
Vest4		0.25
MutPred		0.24		Loss of glycosylation at P3 (P = 0.0312);Loss of glycosylation at P3 (P = 0.0312);
MVP		0.54
MPC		0.11
ClinPred		0.043	T
GERP RS		1.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.087
gMVP		0.62

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: rs1238368716; hg19: chr3-33155577;