NM_006371.5:c.534C>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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.534C>G	p.Asp178Glu	missense_variant	Exon 2 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.534C>G	p.Asp178Glu	missense_variant	Exon 2 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.534C>G	p.Asp178Glu	missense_variant	Exon 2 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.472-4002C>G		intron_variant	Intron 1 of 5		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.534C>G	p.Asp178Glu	missense_variant	Exon 2 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.534C>G	p.Asp178Glu	missense_variant	Exon 2 of 6	2		ENSP00000409997.1
CRTAP	ENST00000485310.1	n.128C>G		non_coding_transcript_exon_variant	Exon 2 of 5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 7 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M;.
PhyloP100		-0.93
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.58		Loss of glycosylation at K174 (P = 0.0545);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;