NM_006371.5:c.732C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_006371.5(CRTAP):c.732C>T(p.Leu244Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 3 hom. )

Consequence

CRTAP
NM_006371.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -4.21

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 7
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
osteogenesis imperfecta type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRTAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.03).

BP6

Variant 3-33124518-C-T is Benign according to our data. Variant chr3-33124518-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284911.

BP7

Synonymous conserved (PhyloP=-4.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (266/152318) while in subpopulation NFE AF = 0.00309 (210/68036). AF 95% confidence interval is 0.00274. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5 link	c.732C>T	p.Leu244Leu	synonymous_variant	Exon 3 of 7	ENST00000320954.11	NP_006362.1	O75718
CRTAP	NM_001393363.1 link	c.732C>T	p.Leu244Leu	synonymous_variant	Exon 3 of 6		NP_001380292.1
CRTAP	NM_001393364.1 link	c.732C>T	p.Leu244Leu	synonymous_variant	Exon 3 of 6		NP_001380293.1
CRTAP	NM_001393365.1 link	c.582C>T	p.Leu194Leu	synonymous_variant	Exon 2 of 6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTAP	ENST00000320954.11 link	c.732C>T	p.Leu244Leu	synonymous_variant	Exon 3 of 7	1	NM_006371.5	ENSP00000323696.5	O75718
CRTAP	ENST00000449224.1 link	c.732C>T	p.Leu244Leu	synonymous_variant	Exon 3 of 6	2		ENSP00000409997.1	C9JP16
CRTAP	ENST00000485310.1 link	n.326C>T		non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00213

AC:

535

AN:

251478

AF XY:

0.00196

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00342

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00271

AC:

3963

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1868

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.00183

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00326

AC:

3627

AN:

1112010

Other (OTH)

AF:

0.00187

AC:

113

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

235

471

706

942

1177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152318

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41558

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00309

AC:

210

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Uncertain:1Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Aug 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CRTAP: BP4, BP7 -

Jul 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis imperfecta

Benign:1

Jul 19, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 07, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CRTAP-related disorder

Benign:1

Mar 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.13

(source)

DANN

Benign

0.53

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over