rs111033552

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-116120105-A-G
• chr6-116120105-A-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. 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
• Publications: 6 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.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 17477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000493.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	NM_000493.4	MANE Select	c.2011T>C	p.Ser671Pro	missense	Exon 3 of 3	NP_000484.2
	NT5DC1	NM_152729.3	MANE Select	c.529+2160A>G		intron	N/A	NP_689942.2
	COL10A1	NM_001424106.1		c.2011T>C	p.Ser671Pro	missense	Exon 3 of 3	NP_001411035.1	A0A650AXN9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	ENST00000651968.1	MANE Select	c.2011T>C	p.Ser671Pro	missense	Exon 3 of 3	ENSP00000498802.1	Q03692
	COL10A1	ENST00000243222.8	TSL:1	c.2011T>C	p.Ser671Pro	missense	Exon 3 of 3	ENSP00000243222.4	Q03692
	COL10A1	ENST00000327673.4	TSL:1	c.2011T>C	p.Ser671Pro	missense	Exon 2 of 2	ENSP00000327368.4	Q03692

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Metaphyseal chondrodysplasia, Schmid type (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.91		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
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs111033552; hg19: chr6-116441268;