chr12-14882147-T-C

Position:

chr12-14882147-T-C

Variant summary

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

The NM_000900.5(MGP):c.304A>G(p.Thr102Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,613,474 control chromosomes in the GnomAD database, including 125,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13894 hom., cov: 30)

Exomes 𝑓: 0.39 ( 111953 hom. )

Consequence

MGP
NM_000900.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.344

Variant links:

Genes affected

MGP (HGNC:7060): (matrix Gla protein) This gene encodes a member of the osteocalcin/matrix Gla family of proteins. The encoded vitamin K-dependent protein is secreted by chondrocytes and vascular smooth muscle cells, and functions as a physiological inhibitor of ectopic tissue calcification. Carboxylation status of the encoded protein is associated with calcification of the vasculature in human patients with cardiovascular disease and calcification of the synovial membranes in osteoarthritis patients. Mutations in this gene cause Keutel syndrome in human patients, which is characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and facial hypoplasia. [provided by RefSeq, Sep 2016]

MGP links:

C12orf60 (HGNC:28726): (chromosome 12 open reading frame 60)

C12orf60 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=4.2084524E-5).

BP6

Variant 12-14882147-T-C is Benign according to our data. Variant chr12-14882147-T-C is described in ClinVar as [Benign]. Clinvar id is 284369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-14882147-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGP	NM_000900.5 linkuse as main transcript	c.304A>G	p.Thr102Ala	missense_variant	4/4	ENST00000539261.6	NP_000891.2
MGP	NM_001190839.3 linkuse as main transcript	c.379A>G	p.Thr127Ala	missense_variant	5/5		NP_001177768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGP	ENST00000539261.6 linkuse as main transcript	c.304A>G	p.Thr102Ala	missense_variant	4/4	1	NM_000900.5	ENSP00000445907	P1	P08493-1

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62884

AN:

151764

Hom.:

13844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.524

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.310

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.409

GnomAD3 exomes

AF:

0.374

AC:

93888

AN:

251124

Hom.:

18546

AF XY:

0.379

AC XY:

51425

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.535

Gnomad AMR exome

AF:

0.368

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.121

Gnomad SAS exome

AF:

0.436

Gnomad FIN exome

AF:

0.307

Gnomad NFE exome

AF:

0.390

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.386

AC:

564712

AN:

1461592

Hom.:

111953

Cov.:

AF XY:

0.388

AC XY:

282208

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.538

Gnomad4 AMR exome

AF:

0.368

Gnomad4 ASJ exome

AF:

0.367

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.435

Gnomad4 FIN exome

AF:

0.310

Gnomad4 NFE exome

AF:

0.392

Gnomad4 OTH exome

AF:

0.381

GnomAD4 genome

AF:

0.415

AC:

62989

AN:

151882

Hom.:

13894

Cov.:

AF XY:

0.410

AC XY:

30430

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.531

Gnomad4 AMR

AF:

0.401

Gnomad4 ASJ

AF:

0.380

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.427

Gnomad4 FIN

AF:

0.310

Gnomad4 NFE

AF:

0.385

Gnomad4 OTH

AF:

0.410

Alfa

AF:

0.397

Hom.:

21932

Bravo

AF:

0.423

TwinsUK

AF:

0.389

AC:

1441

ALSPAC

AF:

0.401

AC:

1544

ESP6500AA

AF:

0.522

AC:

2302

ESP6500EA

AF:

0.394

AC:

3385

ExAC

AF:

0.380

AC:

46119

Asia WGS

AF:

0.304

AC:

1062

AN:

3478

EpiCase

AF:

0.394

EpiControl

AF:

0.403

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 30159058, 24281054, 11073842, 23046575) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Keutel syndrome

Benign:2

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	Sep 05, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.66

DANN

Benign

0.53

DEOGEN2

Benign

0.031

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.000042

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.29

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.019

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.022

MPC

0.21

ClinPred

0.0028

GERP RS

0.16

Varity_R

0.029

gMVP

0.42

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