rs767456804

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_006371.5(CRTAP):c.368A>G(p.Lys123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,576,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K123K) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CRTAP
NM_006371.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.72

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058479905).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000591 (9/152310) while in subpopulation EAS AF = 0.00174 (9/5172). AF 95% confidence interval is 0.000908. There are 0 homozygotes in GnomAd4. There are 5 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1	O75718
CRTAP	NM_001393363.1 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1 link	c.368A>G	p.Lys123Arg	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.368A>G	p.Lys123Arg	missense_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5		O75718
CRTAP	ENST00000449224.1 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 1 of 6	2		ENSP00000409997.1		C9JP16

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

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

GnomAD2 exomes

AF:

0.0000946

AC:

AN:

179612

AF XY:

0.000101

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00119

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000505

AC:

AN:

1424676

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

705832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32480

American (AMR)

AF:

0.00

AC:

AN:

40296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25412

East Asian (EAS)

AF:

0.00178

AC:

AN:

38114

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1095778

Other (OTH)

AF:

0.00

AC:

AN:

58888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000712

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

Jan 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 123 of the CRTAP protein (p.Lys123Arg). This variant is present in population databases (rs767456804, gnomAD 0.1%). 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: 568933). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.058

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

L;.

PhyloP100

8.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.19

T;T

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;D

Vest4

0.62

MutPred

0.23

Loss of methylation at K123 (P = 0.0132);Loss of methylation at K123 (P = 0.0132);

MVP

0.85

MPC

0.097

ClinPred

0.31

GERP RS

3.1

PromoterAI

0.015

Neutral

(source)

Varity_R

0.26

gMVP

0.58

Mutation Taster

=87/13

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