NM_006371.5:c.446A>G

Variant names:

• chr3-33114523-A-G
• rs201564256
• NM_006371.5:c.446A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_006371.5(CRTAP):​c.446A>G​(p.Lys149Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,602,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K149K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.87
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_006371.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.02178064).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000762 (116/152256) while in subpopulation NFE AF = 0.00134 (91/67994). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 46 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 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006371.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	NM_006371.5	MANE Select	c.446A>G	p.Lys149Arg	missense	Exon 1 of 7	NP_006362.1
	CRTAP	NM_001393363.1		c.446A>G	p.Lys149Arg	missense	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.446A>G	p.Lys149Arg	missense	Exon 1 of 6	NP_001380293.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.446A>G	p.Lys149Arg	missense	Exon 1 of 7	ENSP00000323696.5
	CRTAP	ENST00000449224.1	TSL:2	c.446A>G	p.Lys149Arg	missense	Exon 1 of 6	ENSP00000409997.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152142 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000719 AC: 156 AN: 216928 AF XY: 0.000758

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.000756

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.000748

GnomAD4 exome AF: 0.00111 AC: 1612 AN: 1450680 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 849 AN XY: 720828

African (AFR) AF: 0.000180 AC: 6 AN: 33290

American (AMR) AF: 0.000409 AC: 18 AN: 43960

Ashkenazi Jewish (ASJ) AF: 0.000927 AC: 24 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84480

European-Finnish (FIN) AF: 0.000255 AC: 13 AN: 50916

Middle Eastern (MID) AF: 0.000465 AC: 2 AN: 4304

European-Non Finnish (NFE) AF: 0.00132 AC: 1463 AN: 1108598

Other (OTH) AF: 0.00122 AC: 73 AN: 59818

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152256 Hom.: 0 Cov.: 34 AF XY: 0.000618 AC XY: 46 AN XY: 74428

African (AFR) AF: 0.000265 AC: 11 AN: 41566

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000767

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000798 AC: 91

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta type 7 Uncertain:3

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.

Jan 29, 2025

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 149 of the CRTAP protein (p.Lys149Arg). This variant is present in population databases (rs201564256, 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: 344807). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CRTAP protein function with a negative predictive value of 80%. 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.

Mar 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CRTAP c.446A>G; p.Lys149Arg variant (rs201564256), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 344807). This variant is found in the general population with an overall allele frequency of 0.07411% (184/248268 alleles, including 0 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.082). Due to limited information, the clinical significance of this variant is uncertain at this time.

not provided Uncertain:2

May 02, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Apr 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CRTAP c.446A>G (p.Lys149Arg) results in a conservative amino acid change located in the Leprecan-like alpha-helical domain (IPR056585) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 216928 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in CRTAP causing Osteogenesis Imperfecta phenotype (0.0011). To our knowledge, no occurrence of c.446A>G in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 344807). Based on the evidence outlined above, the variant was classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0021
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.082
Sift	Benign	0.77	T
Sift4G	Benign	0.71	T
Polyphen		0.099	B
Vest4		0.25
MVP		0.74
MPC		0.094
ClinPred		0.019	T
GERP RS		4.3
PromoterAI		-0.15	Neutral
Varity_R		0.26
gMVP		0.43
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201564256; hg19: chr3-33156015;