6-116120105-A-G

Variant names:

• chr6-116120105-A-G
• rs111033552
• NM_000493.4:c.2011T>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000493.4(COL10A1):​c.2011T>C​(p.Ser671Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.28

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain C1q (size 133) in uniprot entity COAA1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000493.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 6-116120105-A-G is Pathogenic according to our data. Variant chr6-116120105-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.2011T>C	p.Ser671Pro	missense_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+2160A>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.2011T>C	p.Ser671Pro	missense_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+2160A>G		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Pathogenic:2

Aug 30, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This COL10A1 variant has been previously identified in affected mother and her two affected sons as well as multiple affected individuals in another large family. c.2011T>C is located in the second noncollagenous domain (NC2), a region important to tertiary collagen structure in which many other disease‐associated variants have been identified. This variant is absent from large population datasets and is listed in ClinVar as pathogenic by a single submitter (OMIM). Of three bioinformatics tools queried, two predict that the substitution would be possibly damaging, while one predicts that it would be tolerated. Additionally, the serine residue at this position is evolutionarily conserved across most higher order species assessed. This variant is likely pathogenic in this patient. -

Dec 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jun 07, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29234170, 8986632) -

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 17477). This missense change has been observed in individuals with Schmid metaphyseal chondrodysplasia (PMID: 8986632, 29234170). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 671 of the COL10A1 protein (p.Ser671Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.91		Loss of stability (P = 0.0514);Loss of stability (P = 0.0514);
MVP		0.91
MPC		0.047
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.89

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: rs111033552; hg19: chr6-116441268;