rs111033546

chr6-116120345-A-Cchr6-116120345-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000493.4(COL10A1):c.1771T>G(p.Cys591Gly) variant causes a missense change involving the alteration of a 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C591F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.35

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 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000493.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-116120344-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1683461.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 6-116120345-A-C is Pathogenic according to our data. Variant chr6-116120345-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800885.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-116120345-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL10A1	NM_000493.4	c.1771T>G	p.Cys591Gly	missense_variant	3/3	ENST00000651968.1
NT5DC1	NM_152729.3	c.529+2400A>C		intron_variant		ENST00000319550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL10A1	ENST00000651968.1	c.1771T>G	p.Cys591Gly	missense_variant	3/3		NM_000493.4	P1
NT5DC1	ENST00000319550.9	c.529+2400A>C		intron_variant		1	NM_152729.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Sep 26, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Benign	0.94
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.091	T;T
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.95		Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);
MVP		0.97
MPC		0.047
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.83

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: rs111033546; hg19: chr6-116441508;