NM_000900.5:c.87T>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000900.5(MGP):​c.87T>C​(p.Tyr29Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000611 in 1,308,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: MGP NM_000900.5 synonymous
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.103).
• BP6: Variant 12-14884220-A-G is Benign according to our data. Variant chr12-14884220-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2055589.Status of the report is criteria_provided_single_submitter, 1 stars.

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.87T>C	p.Tyr29Tyr	synonymous	Exon 2 of 4	NP_000891.2
	MGP	NM_001190839.3		c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 5	NP_001177768.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGP	ENST00000539261.6	TSL:1 MANE Select	c.87T>C	p.Tyr29Tyr	synonymous	Exon 2 of 4	ENSP00000445907.1
	MGP	ENST00000507170.2	TSL:1	n.150T>C		non_coding_transcript_exon	Exon 2 of 2
	MGP	ENST00000228938.5	TSL:3	c.162T>C	p.Tyr54Tyr	synonymous	Exon 3 of 5	ENSP00000228938.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000858 AC: 2 AN: 233052 AF XY: 0.00000792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000611 AC: 8 AN: 1308592 Hom.: 0 Cov.: 24 AF XY: 0.00000460 AC XY: 3 AN XY: 651898

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30320

American (AMR) AF: 0.00 AC: 0 AN: 41082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23876

East Asian (EAS) AF: 0.00 AC: 0 AN: 37762

South Asian (SAS) AF: 0.0000376 AC: 3 AN: 79766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 0.00000506 AC: 5 AN: 987480

Other (OTH) AF: 0.00 AC: 0 AN: 54254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000200097), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		1.2
PromoterAI		0.010	Neutral

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: rs730880322; hg19: chr12-15037154;