6-116125413-A-G

Position:

chr6-116125413-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000493.4(COL10A1):c.80T>C(p.Met27Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,613,516 control chromosomes in the GnomAD database, including 133,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M27R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.47 ( 18514 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115298 hom. )

Consequence

COL10A1
NM_000493.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.72

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.0376253E-6).

BP6

Variant 6-116125413-A-G is Benign according to our data. Variant chr6-116125413-A-G is described in ClinVar as [Benign]. Clinvar id is 256262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116125413-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL10A1	NM_000493.4 linkuse as main transcript	c.80T>C	p.Met27Thr	missense_variant	2/3	ENST00000651968.1
NT5DC1	NM_152729.3 linkuse as main transcript	c.529+7468A>G		intron_variant		ENST00000319550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL10A1	ENST00000651968.1 linkuse as main transcript	c.80T>C	p.Met27Thr	missense_variant	2/3		NM_000493.4	P1
NT5DC1	ENST00000319550.9 linkuse as main transcript	c.529+7468A>G		intron_variant		1	NM_152729.3	P1	Q5TFE4-1

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70773

AN:

151934

Hom.:

18483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.427

Gnomad EAS

AF:

0.235

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.358

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.452

GnomAD3 exomes

AF:

0.370

AC:

92932

AN:

251422

Hom.:

19186

AF XY:

0.368

AC XY:

50055

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.231

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.211

Gnomad SAS exome

AF:

0.354

Gnomad FIN exome

AF:

0.362

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.386

GnomAD4 exome

AF:

0.391

AC:

570913

AN:

1461464

Hom.:

115298

Cov.:

AF XY:

0.389

AC XY:

282484

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.723

Gnomad4 AMR exome

AF:

0.244

Gnomad4 ASJ exome

AF:

0.432

Gnomad4 EAS exome

AF:

0.270

Gnomad4 SAS exome

AF:

0.345

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.394

Gnomad4 OTH exome

AF:

0.411

GnomAD4 genome

AF:

0.466

AC:

70842

AN:

152052

Hom.:

18514

Cov.:

AF XY:

0.460

AC XY:

34194

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.715

Gnomad4 AMR

AF:

0.343

Gnomad4 ASJ

AF:

0.427

Gnomad4 EAS

AF:

0.234

Gnomad4 SAS

AF:

0.354

Gnomad4 FIN

AF:

0.358

Gnomad4 NFE

AF:

0.389

Gnomad4 OTH

AF:

0.452

Alfa

AF:

0.395

Hom.:

30581

Bravo

AF:

0.473

TwinsUK

AF:

0.390

AC:

1446

ALSPAC

AF:

0.399

AC:

1538

ESP6500AA

AF:

0.700

AC:

3084

ESP6500EA

AF:

0.393

AC:

3384

ExAC

AF:

0.380

AC:

46186

Asia WGS

AF:

0.392

AC:

1362

AN:

3478

EpiCase

AF:

0.387

EpiControl

AF:

0.390

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Metaphyseal chondrodysplasia, Schmid type

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.47

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.10

T;.;T;T

MetaRNN

Benign

0.0000020

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.69

N;N;.;.

MutationTaster

Benign

0.011

P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

0.34

N;N;N;N

REVEL

Benign

0.27

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.74

T;T;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.095

MPC

0.0078

ClinPred

0.0050

GERP RS

6.1

Varity_R

0.071

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over