3-33114523-A-G

Position:

• chr3-33114523-A-G

Variant summary

Our verdict is Benign. Variant got -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. 12/21 in silico tools predict 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. 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: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.87

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]

ACMG classification

Verdict is Benign. Variant got -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, 8 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.446A>G	p.Lys149Arg	missense_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.446A>G	p.Lys149Arg	missense_variant	1/6
CRTAP	NM_001393364.1	c.446A>G	p.Lys149Arg	missense_variant	1/6
CRTAP	NM_001393365.1	c.446A>G	p.Lys149Arg	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.446A>G	p.Lys149Arg	missense_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.446A>G	p.Lys149Arg	missense_variant	1/6	2

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

GnomAD3 exomes AF: 0.000719 AC: 156 AN: 216928 Hom.: 0 AF XY: 0.000758 AC XY: 91 AN XY: 120002

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 SAS exome AF: 0.000213

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

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000409

Gnomad4 ASJ exome AF: 0.000927

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.000255

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.00122

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00121 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: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Osteogenesis imperfecta type 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	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). 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 not 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0021
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.082
Sift	Benign	0.77	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.099	B;B
Vest4		0.25
MVP		0.74
MPC		0.094
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.26
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs201564256; hg19: chr3-33156015;