10-97895299-C-T

Position:

• chr10-97895299-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018058.7(CRTAC1):​c.1432G>A​(p.Asp478Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CRTAC1 NM_018058.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

Genes affected

CRTAC1 (HGNC:14882): (cartilage acidic protein 1) This gene encodes a glycosylated extracellular matrix protein that is found in the interterritorial matrix of articular deep zone cartilage. This protein is used as a marker to distinguish chondrocytes from osteoblasts and mesenchymal stem cells in culture. The presence of FG-GAP motifs and an RGD integrin-binding motif suggests that this protein may be involved in cell-cell or cell-matrix interactions. Copy number alterations in this gene have been observed in neurofibromatosis type 1-associated glomus tumors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTAC1	NM_018058.7	c.1432G>A	p.Asp478Asn	missense_variant	11/15	ENST00000370597.8	NP_060528.3
CRTAC1	NM_001206528.3	c.1432G>A	p.Asp478Asn	missense_variant	11/15		NP_001193457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTAC1	ENST00000370597.8	c.1432G>A	p.Asp478Asn	missense_variant	11/15	1	NM_018058.7	ENSP00000359629.3
CRTAC1	ENST00000309155.3	c.1408G>A	p.Asp470Asn	missense_variant	10/14	1		ENSP00000310810.3
CRTAC1	ENST00000370591.6	c.1432G>A	p.Asp478Asn	missense_variant	11/15	5		ENSP00000359623.2
CRTAC1	ENST00000413387.5	c.1120G>A	p.Asp374Asn	missense_variant	9/12	2		ENSP00000408445.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727022

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.1432G>A (p.D478N) alteration is located in exon 11 (coding exon 11) of the CRTAC1 gene. This alteration results from a G to A substitution at nucleotide position 1432, causing the aspartic acid (D) at amino acid position 478 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.091	T;D;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.2	.;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.16	T;T;T;D
Sift4G	Uncertain	0.058	T;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.92, 0.93
MutPred		0.70		.;Gain of MoRF binding (P = 0.045);Gain of MoRF binding (P = 0.045);.;
MVP		0.85
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.31
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-99655056;