rs111033547

Positions:

• chr6-116120163-C-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.1953G>A​(p.Trp651*) variant causes a stop gained 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 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.37

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 0.0441 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-116120163-C-T is Pathogenic according to our data. Variant chr6-116120163-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17473.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.1953G>A	p.Trp651*	stop_gained	3/3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+2218C>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.1953G>A	p.Trp651*	stop_gained	3/3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+2218C>T		intron_variant		1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.80
GERP RS		5.0

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: rs111033547; hg19: chr6-116441326;