chr12-14882170-C-A

Variant names:

• chr12-14882170-C-A
• rs546998085
• NM_000900.5:c.281G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000900.5(MGP):​c.281G>T​(p.Arg94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MGP NM_000900.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGP	NM_000900.5	MANE Select	c.281G>T	p.Arg94Leu	missense	Exon 4 of 4	NP_000891.2
	MGP	NM_001190839.3		c.356G>T	p.Arg119Leu	missense	Exon 5 of 5	NP_001177768.1	P08493-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGP	ENST00000539261.6	TSL:1 MANE Select	c.281G>T	p.Arg94Leu	missense	Exon 4 of 4	ENSP00000445907.1	P08493-1
	MGP	ENST00000228938.5	TSL:3	c.356G>T	p.Arg119Leu	missense	Exon 5 of 5	ENSP00000228938.5	P08493-2
	MGP	ENST00000905127.1		c.281G>T	p.Arg94Leu	missense	Exon 5 of 5	ENSP00000575186.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251172 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461818 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.55		Loss of MoRF binding (P = 0.05)
MVP		1.0
MPC		0.88
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.79
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs546998085; hg19: chr12-15035104;