chr6-116120326-T-C

Position:

• chr6-116120326-T-C

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.1790A>G​(p.Tyr597Cys) variant causes a missense 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y597H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.17

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 region_of_interest Nonhelical region (NC1) (size 160) 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 6-116120326-T-C is Pathogenic according to our data. Variant chr6-116120326-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 17480.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.1790A>G	p.Tyr597Cys	missense_variant	3/3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+2381T>C		intron_variant		ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.1790A>G	p.Tyr597Cys	missense_variant	3/3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+2381T>C		intron_variant		1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.11	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.97		Loss of catalytic residue at I596 (P = 0.0605);Loss of catalytic residue at I596 (P = 0.0605);
MVP		1.0
MPC		0.047
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.80

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: rs111033554; hg19: chr6-116441489;