NM_000493.4:c.80T>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2

The NM_000493.4(COL10A1):c.80T>G(p.Met27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M27T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

COL10A1
NM_000493.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

Publications

58 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000103 (15/1461588) while in subpopulation EAS AF = 0.000378 (15/39632). AF 95% confidence interval is 0.000233. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4 link	c.80T>G	p.Met27Arg	missense_variant	Exon 2 of 3	ENST00000651968.1	NP_000484.2	Q03692A0A650AXN9
NT5DC1	NM_152729.3 link	c.529+7468A>C		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2	Q5TFE4-1Q9H2R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1 link	c.80T>G	p.Met27Arg	missense_variant	Exon 2 of 3		NM_000493.4	ENSP00000498802.1		Q03692
NT5DC1	ENST00000319550.9 link	c.529+7468A>C		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3		Q5TFE4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000378

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111850

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;T;.;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.20

T;.;T;T

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.0

N;N;.;.

PhyloP100

2.7

PrimateAI

Benign

0.47

PROVEAN

Benign

0.41

N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.15

T;T;D;D

Sift4G

Benign

0.67

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.17

MutPred

0.73

Gain of disorder (P = 0.0466);Gain of disorder (P = 0.0466);Gain of disorder (P = 0.0466);Gain of disorder (P = 0.0466);

MVP

0.86

MPC

0.0076

ClinPred

0.74

GERP RS

6.1

PromoterAI

0.010

Neutral

(source)

Varity_R

0.19

gMVP

0.55

Mutation Taster

=99/1

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over