6-116120220-G-T

Variant names:

• chr6-116120220-G-T
• rs111033548
• NM_000493.4:c.1896C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000493.4(COL10A1):​c.1896C>A​(p.Tyr632*) 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
• Publications: 5 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 12 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. There are 29 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 VariationId is 17478.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	NM_000493.4	MANE Select	c.1896C>A	p.Tyr632*	stop_gained	Exon 3 of 3	NP_000484.2
	NT5DC1	NM_152729.3	MANE Select	c.529+2275G>T		intron	N/A	NP_689942.2
	COL10A1	NM_001424106.1		c.1896C>A	p.Tyr632*	stop_gained	Exon 3 of 3	NP_001411035.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	ENST00000651968.1	MANE Select	c.1896C>A	p.Tyr632*	stop_gained	Exon 3 of 3	ENSP00000498802.1
	COL10A1	ENST00000243222.8	TSL:1	c.1896C>A	p.Tyr632*	stop_gained	Exon 3 of 3	ENSP00000243222.4
	COL10A1	ENST00000327673.4	TSL:1	c.1896C>A	p.Tyr632*	stop_gained	Exon 2 of 2	ENSP00000327368.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Metaphyseal chondrodysplasia, Schmid type (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.6
Vest4		0.81
GERP RS		1.9
Mutation Taster		=1/199	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: rs111033548; hg19: chr6-116441383;