Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000493.4(COL10A1):c.1951T>C(p.Trp651Arg) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W651L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

COL10A1
NM_000493.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32

Publications

4 publications found

Variant links:

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]

COL10A1 links:

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]

NT5DC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000493.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 6-116120165-A-G is Pathogenic according to our data. Variant chr6-116120165-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 17474.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL10A1	NM_000493.4	MANE Select	c.1951T>C	p.Trp651Arg	missense	Exon 3 of 3	NP_000484.2
NT5DC1	NM_152729.3	MANE Select	c.529+2220A>G		intron	N/A	NP_689942.2
COL10A1	NM_001424106.1		c.1951T>C	p.Trp651Arg	missense	Exon 3 of 3	NP_001411035.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL10A1	ENST00000651968.1	MANE Select	c.1951T>C	p.Trp651Arg	missense	Exon 3 of 3	ENSP00000498802.1
COL10A1	ENST00000243222.8	TSL:1	c.1951T>C	p.Trp651Arg	missense	Exon 3 of 3	ENSP00000243222.4
COL10A1	ENST00000327673.4	TSL:1	c.1951T>C	p.Trp651Arg	missense	Exon 2 of 2	ENSP00000327368.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Metaphyseal chondrodysplasia, Schmid type (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.3

PhyloP100

9.3

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.89

Sift

Uncertain

0.011

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.73

MutPred

0.91

Gain of disorder (P = 0.0199)

MVP

0.99

MPC

0.044

ClinPred

0.99

GERP RS

5.0

Varity_R

0.89

gMVP

0.83

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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NM_000493.4:c.1951T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over