chr3-33120406-C-G

Variant names:

• chr3-33120406-C-G
• rs4076086
• NM_006371.5:c.534C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006371.5(CRTAP):​c.534C>G​(p.Asp178Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D178D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.934
• Publications: 31 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

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.534C>G	p.Asp178Glu	missense	Exon 2 of 7	NP_006362.1
	CRTAP	NM_001393363.1		c.534C>G	p.Asp178Glu	missense	Exon 2 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.534C>G	p.Asp178Glu	missense	Exon 2 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.534C>G	p.Asp178Glu	missense	Exon 2 of 7	ENSP00000323696.5
	CRTAP	ENST00000449224.1	TSL:2	c.534C>G	p.Asp178Glu	missense	Exon 2 of 6	ENSP00000409997.1
	CRTAP	ENST00000485310.1	TSL:4	n.128C>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Osteogenesis imperfecta type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	1.4
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-0.93
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.58		Loss of glycosylation at K174 (P = 0.0545)
MVP		0.71
MPC		0.40
ClinPred		0.87	D
GERP RS		-7.1
Varity_R		0.13
gMVP		0.61
Mutation Taster		=50/50

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: rs4076086; hg19: chr3-33161898;