chr12-14881796-C-T

Variant names:

• chr12-14881796-C-T
• rs35112962
• NM_000900.5:c.*343G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000900.5(MGP):​c.*343G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 264,692 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: MGP NM_000900.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-14881796-C-T is Benign according to our data. Variant chr12-14881796-C-T is described in ClinVar as Benign. ClinVar VariationId is 307763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1952/152076) while in subpopulation AFR AF = 0.0446 (1851/41478). AF 95% confidence interval is 0.0429. There are 44 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

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.*343G>A		3_prime_UTR	Exon 4 of 4	NP_000891.2
	MGP	NM_001190839.3		c.*343G>A		3_prime_UTR	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.*343G>A		3_prime_UTR	Exon 4 of 4	ENSP00000445907.1	P08493-1
	C12orf60	ENST00000527783.1	TSL:2	n.76-17373C>T		intron	N/A
	C12orf60	ENST00000533472.1	TSL:3	n.87-22211C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1951 AN: 151958 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00910

GnomAD4 exome AF: 0.00133 AC: 150 AN: 112616 Hom.: 2 Cov.: 0 AF XY: 0.00121 AC XY: 73 AN XY: 60180

African (AFR) AF: 0.0355 AC: 123 AN: 3460

American (AMR) AF: 0.00110 AC: 6 AN: 5432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2910

East Asian (EAS) AF: 0.00 AC: 0 AN: 6232

South Asian (SAS) AF: 0.00 AC: 0 AN: 17200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 392

European-Non Finnish (NFE) AF: 0.000135 AC: 9 AN: 66436

Other (OTH) AF: 0.00208 AC: 12 AN: 5770

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152076 Hom.: 44 Cov.: 32 AF XY: 0.0123 AC XY: 917 AN XY: 74314

African (AFR) AF: 0.0446 AC: 1851 AN: 41478

American (AMR) AF: 0.00445 AC: 68 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68010

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00399 Hom.: 15

Bravo AF: 0.0146

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.45
PhyloP100		0.50
Mutation Taster		=100/0	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: rs35112962; hg19: chr12-15034730;