rs201564256

Positions:

• chr3-33114523-A-C
• chr3-33114523-A-G
• chr3-33114523-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006371.5(CRTAP):​c.446A>C​(p.Lys149Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,450,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K149R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.446A>C	p.Lys149Thr	missense_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.446A>C	p.Lys149Thr	missense_variant	1/6
CRTAP	NM_001393364.1	c.446A>C	p.Lys149Thr	missense_variant	1/6
CRTAP	NM_001393365.1	c.446A>C	p.Lys149Thr	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.446A>C	p.Lys149Thr	missense_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.446A>C	p.Lys149Thr	missense_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450684 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T;D
Sift4G	Uncertain	0.052	T;T
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.41		Loss of methylation at K149 (P = 2e-04);Loss of methylation at K149 (P = 2e-04);
MVP		0.82
MPC		0.22
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;