NM_000900.5:c.87T>A

Variant names:

• chr12-14884220-A-T
• rs730880322
• NM_000900.5:c.87T>A
• MGP p.Tyr29*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5

The NM_000900.5(MGP):c.87T>A (p.Tyr29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MGP NM_000900.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.16
• Publications: 0 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]

MGP Gene-Disease associations (from GenCC):

• Keutel syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• skeletal dysplasia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

C12orf60 (HGNC:28726): ()

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 2 of 4) at amino acid 29 of 103, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MGP NM_000900.5	MANE Select	c.87T>A p.Tyr29*	stop_gained	Exon 2 of 4	Prot: NP_000891.2
	MGP NM_001190839.3		c.162T>A p.Tyr54*	stop_gained	Exon 3 of 5	Prot: NP_001177768.1 UniProt:

MGP NM_000900.5

MANE Select

HGVSc / HGVSpc.87T>Ap.Tyr29*

Exon rankExon 2 of 4

stop_gained

Prot: NP_000891.2

MGP NM_001190839.3

HGVSc / HGVSpc.162T>Ap.Tyr54*

Exon rankExon 3 of 5

stop_gained

Prot: NP_001177768.1UniProt: P08493-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MGP ENST00000539261.6	TSL:1MANE Select	c.87T>A p.Tyr29*	stop_gained	Exon 2 of 4	Prot: ENSP00000445907.1 UniProt:
	MGP ENST00000507170.2	TSL:1	n.150T>A	non_coding_transcript_exon	Exon 2 of 2	Prot:
	MGP ENST00000228938.5	TSL:3	c.162T>A p.Tyr54*	stop_gained	Exon 3 of 5	Prot: ENSP00000228938.5 UniProt:

MGP ENST00000539261.6

TSL:1MANE Select

HGVSc / HGVSpc.87T>Ap.Tyr29*

Exon rankExon 2 of 4

stop_gained

Prot: ENSP00000445907.1UniProt: P08493-1

MGP ENST00000507170.2

TSL:1

HGVSc / HGVSpn.150T>A

Exon rankExon 2 of 2

non_coding_transcript_exon

Prot:

MGP ENST00000228938.5

TSL:3

HGVSc / HGVSpc.162T>Ap.Tyr54*

Exon rankExon 3 of 5

stop_gained

Prot: ENSP00000228938.5UniProt: P08493-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1308592	Cov:24
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Keutel syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	32
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.73	D
GPN-Star LLR	N/A	-6.2
GPN-Star score	N/A	6.2
Mutation Taster	N/A	12/188	disease causing (ClinVar)
PhyloP100	Benign	1.2
PromoterAI	N/A	0.016	Neutral

Showing 13 of 13 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2
Splicevardb	N/A	2.0

Showing 3 of 3 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs730880322;

hg19: chr12-15037154;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar