NM_000493.4:c.52G>C

Variant names:

• chr6-116125441-C-G
• rs111033550
• NM_000493.4:c.52G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000493.4(COL10A1):​c.52G>C​(p.Gly18Arg) variant causes a missense change. 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.10
• Publications: 0 publications found

Genes affected

COL10A1 (HGNC:2185): (collagen type X alpha 1 chain) This gene encodes the alpha chain of type X collagen, a short chain collagen expressed by hypertrophic chondrocytes during endochondral ossification. Unlike type VIII collagen, the other short chain collagen, type X collagen is a homotrimer. Mutations in this gene are associated with Schmid type metaphyseal chondrodysplasia (SMCD) and Japanese type spondylometaphyseal dysplasia (SMD). [provided by RefSeq, Jul 2008]

NT5DC1 (HGNC:21556): (5'-nucleotidase domain containing 1) While the exact function of the protein encoded by this gene is not known, it belongs to the 5'(3')-deoxyribonucleotidase family. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000493.4 (COL10A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-116125440-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17476.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 6-116125441-C-G is Pathogenic according to our data. Variant chr6-116125441-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2807922.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.52G>C	p.Gly18Arg	missense_variant	Exon 2 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+7496C>G		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.52G>C	p.Gly18Arg	missense_variant	Exon 2 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+7496C>G		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 18 of the COL10A1 protein (p.Gly18Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Schmid type Metaphyseal chondrodysplasia (PMID: 9067753, 15024737; Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL10A1 protein function. This variant disrupts the p.Gly18 amino acid residue in COL10A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9067753; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T;.;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	0.81	L;L;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D;D;N;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.88
MutPred		0.96		Loss of catalytic residue at H17 (P = 0.119);Loss of catalytic residue at H17 (P = 0.119);Loss of catalytic residue at H17 (P = 0.119);Loss of catalytic residue at H17 (P = 0.119);
MVP		0.98
MPC		0.0078
ClinPred		0.97	D
GERP RS		5.2
PromoterAI		0.017	Neutral
Varity_R		0.60
gMVP		0.51
Mutation Taster		=16/84	disease causing

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: rs111033550; hg19: chr6-116446604;