Genetic Variant NM_000493.4:c.1771T>C (chr6-116120345-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000493.4(COL10A1):c.1771T>C(p.Cys591Arg) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C591G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL10A1
NM_000493.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.35

Publications

3 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 12 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain 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 chr6-116120345-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 800885.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 6-116120345-A-G is Pathogenic according to our data. Variant chr6-116120345-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 17467.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	UniProt
COL10A1	NM_000493.4	MANE Select	c.1771T>C	p.Cys591Arg	missense	Exon 3 of 3	NP_000484.2
NT5DC1	NM_152729.3	MANE Select	c.529+2400A>G		intron	N/A	NP_689942.2
COL10A1	NM_001424106.1		c.1771T>C	p.Cys591Arg	missense	Exon 3 of 3	NP_001411035.1	A0A650AXN9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL10A1	ENST00000651968.1	MANE Select	c.1771T>C	p.Cys591Arg	missense	Exon 3 of 3	ENSP00000498802.1	Q03692
COL10A1	ENST00000243222.8	TSL:1	c.1771T>C	p.Cys591Arg	missense	Exon 3 of 3	ENSP00000243222.4	Q03692
COL10A1	ENST00000327673.4	TSL:1	c.1771T>C	p.Cys591Arg	missense	Exon 2 of 2	ENSP00000327368.4	Q03692

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely 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

0.95

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.0

PhyloP100

7.4

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.90

Sift

Uncertain

0.017

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.96

MutPred

0.97

Gain of disorder (P = 0.0295)

MVP

0.98

MPC

0.044

ClinPred

1.0

GERP RS

4.7

Varity_R

0.99

gMVP

0.89

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over