3-33120430-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006371.5(CRTAP):c.558A>G(p.Ala186Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,613,268 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A186A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 171 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 180 hom. )

Consequence

CRTAP
NM_006371.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.14

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-33120430-A-G is Benign according to our data. Variant chr3-33120430-A-G is described in ClinVar as Benign. ClinVar VariationId is 195266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5 link	c.558A>G	p.Ala186Ala	synonymous_variant	Exon 2 of 7	ENST00000320954.11	NP_006362.1	O75718
CRTAP	NM_001393363.1 link	c.558A>G	p.Ala186Ala	synonymous_variant	Exon 2 of 6		NP_001380292.1
CRTAP	NM_001393364.1 link	c.558A>G	p.Ala186Ala	synonymous_variant	Exon 2 of 6		NP_001380293.1
CRTAP	NM_001393365.1 link	c.472-3978A>G		intron_variant	Intron 1 of 5		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTAP	ENST00000320954.11 link	c.558A>G	p.Ala186Ala	synonymous_variant	Exon 2 of 7	1	NM_006371.5	ENSP00000323696.5	O75718
CRTAP	ENST00000449224.1 link	c.558A>G	p.Ala186Ala	synonymous_variant	Exon 2 of 6	2		ENSP00000409997.1	C9JP16
CRTAP	ENST00000485310.1 link	n.152A>G		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4186

AN:

152198

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0928

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0173

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.00822

AC:

2046

AN:

249022

AF XY:

0.00605

show subpopulations

Gnomad AFR exome

AF:

0.0921

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.00349

AC:

5102

AN:

1460952

Hom.:

180

Cov.:

AF XY:

0.00311

AC XY:

2257

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.0963

AC:

3223

AN:

33454

American (AMR)

AF:

0.00521

AC:

233

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.0185

AC:

736

AN:

39692

South Asian (SAS)

AF:

0.000638

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000301

AC:

335

AN:

1111176

Other (OTH)

AF:

0.00784

AC:

473

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

259

519

778

1038

1297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.0276

AC:

4198

AN:

152316

Hom.:

171

Cov.:

AF XY:

0.0264

AC XY:

1970

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0928

AC:

3857

AN:

41546

American (AMR)

AF:

0.0104

AC:

159

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0173

AC:

AN:

5192

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68032

Other (OTH)

AF:

0.0189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

195

390

586

781

976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0208

Hom.:

113

Bravo

AF:

0.0309

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Benign:3

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Apr 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Osteogenesis imperfecta

Benign:1

Jun 18, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.027

(source)

DANN

Benign

0.45

PhyloP100

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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