12-14882147-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.344

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]

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

ACMG classification

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	UniProt
MGP	NM_000900.5	c.304A>G	p.Thr102Ala	missense_variant	4/4	ENST00000539261.6
MGP	NM_001190839.3	c.379A>G	p.Thr127Ala	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGP	ENST00000539261.6	c.304A>G	p.Thr102Ala	missense_variant	4/4	1	NM_000900.5	P1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62884 AN: 151764 Hom.: 13844 Cov.: 30

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

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.: 49 AF XY: 0.388 AC XY: 282208 AN XY: 727116

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.: 30 AF XY: 0.410 AC XY: 30430 AN XY: 74214

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Keutel syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -

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	T
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	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.000042	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.29	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs4236; hg19: chr12-15035081; COSMIC: COSV57453935; COSMIC: COSV57453935;