chr6-116120220-G-T

Position:

• chr6-116120220-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000493.4(COL10A1):​c.1896C>A​(p.Tyr632Ter) variant causes a stop gained 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.58

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.072 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-116120220-G-T is Pathogenic according to our data. Variant chr6-116120220-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 17478.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.1896C>A	p.Tyr632Ter	stop_gained	3/3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+2275G>T		intron_variant		ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.1896C>A	p.Tyr632Ter	stop_gained	3/3		NM_000493.4	ENSP00000498802	P1
NT5DC1	ENST00000319550.9	c.529+2275G>T		intron_variant		1	NM_152729.3	ENSP00000326858	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change creates a premature translational stop signal (p.Tyr632*) in the COL10A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the COL10A1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of autosomal dominant metaphyseal chondrodysplasia, Schmid type (PMID: 9708440, 12554676, 20872587). ClinVar contains an entry for this variant (Variation ID: 17478). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects COL10A1 function (PMID: 12554676, 20872587). This variant is located in a region of the COL10A1 protein where a significant number of COL10A1 nonsense and frameshift mutations have been reported in association with autosomal dominant metaphyseal chondrodysplasia (PMID: 21447328, 33764685, 36400164). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.81
GERP RS		1.9

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: rs111033548; hg19: chr6-116441383;