3-33114094-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006371.5(CRTAP):c.17G>T(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,459,814 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. R6R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

CRTAP
NM_006371.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.118

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08677623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CRTAP	NM_006371.5 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/6
CRTAP	NM_001393364.1 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/6
CRTAP	NM_001393365.1 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1 linkuse as main transcript	c.17G>T	p.Arg6Leu	missense_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

73804

Hom.:

AF XY:

0.0000232

AC XY:

AN XY:

43124

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000344

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000803

AC:

105

AN:

1307878

Hom.:

Cov.:

AF XY:

0.0000790

AC XY:

AN XY:

645616

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:

0.0000947

Gnomad4 OTH exome

AF:

0.0000739

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151936

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000127

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 6 of the CRTAP protein (p.Arg6Leu). This variant is present in population databases (rs780490905, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1348476). 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

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Benign

0.76

DEOGEN2

Benign

0.096

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.087

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.029

Sift

Benign

0.091

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0060

B;B

Vest4

0.16

MutPred

0.31

Loss of glycosylation at P3 (P = 0.0312);Loss of glycosylation at P3 (P = 0.0312);

MVP

0.30

MPC

0.14

ClinPred

0.051

GERP RS

1.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.0

Varity_R

0.082

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over