rs202118861

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5BS1_SupportingBS2

The NM_006371.5(CRTAP):c.451C>G(p.Leu151Val) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,602,454 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L151P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00069 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

CRTAP
NM_006371.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.79

Publications

3 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: Likely_benign. The variant received -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-33114529-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1510318.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000689 (105/152358) while in subpopulation NFE AF = 0.00123 (84/68032). AF 95% confidence interval is 0.00102. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1	O75718
CRTAP	NM_001393363.1 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5		O75718
CRTAP	ENST00000449224.1 link	c.451C>G	p.Leu151Val	missense_variant	Exon 1 of 6	2		ENSP00000409997.1		C9JP16

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.00123

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000529

AC:

114

AN:

215494

AF XY:

0.000504

show subpopulations

Gnomad AFR exome

AF:

0.000170

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000974

Gnomad OTH exome

AF:

0.000564

GnomAD4 exome

AF:

0.00130

AC:

1890

AN:

1450096

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

883

AN XY:

720512

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33300

American (AMR)

AF:

0.000729

AC:

AN:

43892

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.00

AC:

AN:

84390

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4292

European-Non Finnish (NFE)

AF:

0.00161

AC:

1788

AN:

1108324

Other (OTH)

AF:

0.00107

AC:

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.000689

AC:

105

AN:

152358

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41588

American (AMR)

AF:

0.000849

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00123

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00116

Hom.:

Bravo

AF:

0.000820

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.000368

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 7

Uncertain:6

Oct 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 151 of the CRTAP protein (p.Leu151Val). This variant is present in population databases (rs202118861, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 429858). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRTAP protein function. 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. -

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. -

Sep 01, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CRTAP c.451C>G; p.Leu151Val variant (rs202118861), to our knowledge, has not been described in the medical literature but is listed as a variant of uncertain significance in ClinVar (Variation ID: 429858). It is observed in the general population at an overall frequency of 0.053% (131/246878 alleles) in the Genome Aggregation Database. The leucine at codon 151 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Another variant at this codon position (c.452T>C; p.Leu151Pro) has been described homozygously in an individual affected with osteogenesis imperfect type 3, though it is unclear if this variant was causative for the phenotype in this patient (Caparros-Martin 2016). Due to limited information regarding the p.Leu151Val variant, its clinical significance cannot be determined with certainty. REFERENCES Caparros-Martin J et al. Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. Mol Genet Genomic Med. 2016 Dec 20;5(1):28-39. -

not provided

Uncertain:1Benign:1

Nov 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CRTAP: PM5:Supporting, BS2 -

Osteogenesis imperfecta

Uncertain:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

3.8

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.99

D;D

Vest4

0.84

MVP

0.65

MPC

0.54

ClinPred

0.11

GERP RS

4.2

PromoterAI

-0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.71

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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