3-33114090-C-T

Variant names:

• chr3-33114090-C-T
• rs758652009
• NM_006371.5:c.13C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006371.5(CRTAP):​c.13C>T​(p.Arg5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,309,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10839626).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	NM_006371.5	MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 6	NP_001380293.1	C9JP16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.13C>T	p.Arg5Cys	missense	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.13C>T	p.Arg5Cys	missense	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000145 AC: 19 AN: 1309076 Hom.: 0 Cov.: 31 AF XY: 0.0000108 AC XY: 7 AN XY: 646254

African (AFR) AF: 0.0000381 AC: 1 AN: 26216

American (AMR) AF: 0.00 AC: 0 AN: 23446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22548

East Asian (EAS) AF: 0.00 AC: 0 AN: 28702

South Asian (SAS) AF: 0.00 AC: 0 AN: 70894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4510

European-Non Finnish (NFE) AF: 0.0000172 AC: 18 AN: 1045748

Other (OTH) AF: 0.00 AC: 0 AN: 54140

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.21
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.067
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.44		Loss of glycosylation at R3 (P = 0.0312)
MVP		0.33
MPC		0.16
ClinPred		0.23	T
GERP RS		0.59
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.0
Varity_R		0.15
gMVP		0.58
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs758652009; hg19: chr3-33155582;