rs772784211

Variant names:

• chr3-33114208-T-C
• rs772784211
• NM_006371.5:c.131T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006371.5(CRTAP):​c.131T>C​(p.Leu44Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000694 in 1,441,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.73

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 6		NP_001380292.1
CRTAP	NM_001393364.1	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 6		NP_001380293.1
CRTAP	NM_001393365.1	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.131T>C	p.Leu44Pro	missense_variant	Exon 1 of 6	2		ENSP00000409997.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000706 AC: 15 AN: 212530 Hom.: 0 AF XY: 0.0000676 AC XY: 8 AN XY: 118392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000894

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000694 AC: 10 AN: 1441804 Hom.: 0 Cov.: 32 AF XY: 0.00000697 AC XY: 5 AN XY: 717260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000230

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.0000424 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131T>C (p.L44P) alteration is located in exon 1 (coding exon 1) of the CRTAP gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Osteogenesis imperfecta type 7 Uncertain:1

Sep 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 44 of the CRTAP protein (p.Leu44Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs772784211, ExAC 0.09%). This variant has not been reported in the literature in individuals with CRTAP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	0.064
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.070	T;D
Sift4G	Uncertain	0.054	T;T
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.51		Gain of glycosylation at Y48 (P = 0.0116);Gain of glycosylation at Y48 (P = 0.0116);
MVP		0.49
MPC		0.71
ClinPred		0.35	T
GERP RS		2.0
Varity_R		0.74
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs772784211; hg19: chr3-33155700;