rs730880322

Variant names:

• chr12-14884220-A-G
• rs730880322
• NM_000900.5:c.87T>C
• MGP p.Tyr29Tyr

Your query was ambiguous. Multiple possible variants found:

• chr12-14884220-A-G
• chr12-14884220-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The ENST00000527783.1(C12orf60):n.76-14949A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000527783.1 is not a MANE Select or MANE Plus Clinical transcript for C12orf60; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000999, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. 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 Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: C12orf60 ENST00000527783.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B: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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000010, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000527783.1. 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>C p.Tyr29Tyr	synonymous	Exon 2 of 4	Prot: NP_000891.2
	MGP NM_001190839.3		c.162T>C p.Tyr54Tyr	synonymous	Exon 3 of 5	Prot: NP_001177768.1 UniProt:

MGP NM_000900.5

MANE Select

HGVSc / HGVSpc.87T>Cp.Tyr29Tyr

Exon rankExon 2 of 4

synonymous

Prot: NP_000891.2

MGP NM_001190839.3

HGVSc / HGVSpc.162T>Cp.Tyr54Tyr

Exon rankExon 3 of 5

synonymous

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>C p.Tyr29Tyr	synonymous	Exon 2 of 4	Prot: ENSP00000445907.1 UniProt:
	MGP ENST00000507170.2	TSL:1	n.150T>C	non_coding_transcript_exon	Exon 2 of 2	Prot:
	MGP ENST00000228938.5	TSL:3	c.162T>C p.Tyr54Tyr	synonymous	Exon 3 of 5	Prot: ENSP00000228938.5 UniProt:
	MGP ENST00000905127.1		c.87T>C p.Tyr29Tyr	synonymous	Exon 3 of 5	Prot: ENSP00000575186.1 UniProt:
	MGP ENST00000545199.5	TSL:3	c.24T>C p.Tyr8Tyr	synonymous	Exon 1 of 2	Prot: ENSP00000445436.1 UniProt:
	C12orf60 ENST00000527783.1	TSL:2	n.76-14949A>G	intron	Intron 1 of 3	Prot:
	C12orf60 ENST00000533472.1	TSL:3	n.87-19787A>G	intron	Intron 1 of 1	Prot:
	C12orf60 ENST00000648334.1		n.126-19787A>G	intron	Intron 2 of 2	Prot:

MGP ENST00000539261.6

TSL:1MANE Select

HGVSc / HGVSpc.87T>Cp.Tyr29Tyr

Exon rankExon 2 of 4

synonymous

Prot: ENSP00000445907.1UniProt: P08493-1

MGP ENST00000507170.2

TSL:1

HGVSc / HGVSpn.150T>C

Exon rankExon 2 of 2

non_coding_transcript_exon

Prot:

MGP ENST00000228938.5

TSL:3

HGVSc / HGVSpc.162T>Cp.Tyr54Tyr

Exon rankExon 3 of 5

synonymous

Prot: ENSP00000228938.5UniProt: P08493-2

MGP ENST00000905127.1

HGVSc / HGVSpc.87T>Cp.Tyr29Tyr

Exon rankExon 3 of 5

synonymous

Prot: ENSP00000575186.1UniProt: P08493-1

MGP ENST00000545199.5

TSL:3

HGVSc / HGVSpc.24T>Cp.Tyr8Tyr

Exon rankExon 1 of 2

synonymous

Prot: ENSP00000445436.1UniProt: H0YGZ6

C12orf60 ENST00000527783.1

TSL:2

HGVSc / HGVSpn.76-14949A>G

Exon rankIntron 1 of 3

intron

Prot:

C12orf60 ENST00000533472.1

TSL:3

HGVSc / HGVSpn.87-19787A>G

Exon rankIntron 1 of 1

intron

Prot:

C12orf60 ENST00000648334.1

HGVSc / HGVSpn.126-19787A>G

Exon rankIntron 2 of 2

intron

Prot:

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000858	AC:2	Hom:	AN:233052	Cov:
GnomAD4 exome Warning	AF: 0.00000611	AC:8	Hom:0	AN:1308592	Cov:24
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.6
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.0
DANN	Benign	0.75
GPN-Star LLR	N/A	-0.48
GPN-Star score	N/A	0.48
PhyloP100	Benign	1.2
PromoterAI	N/A	0.010	Neutral

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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