12-14882112-A-C

Position:

• chr12-14882112-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000900.5(MGP):​c.*27T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,832 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (138 hom.)
• Consequence: MGP NM_000900.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.917

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-14882112-A-C is Benign according to our data. Variant chr12-14882112-A-C is described in ClinVar as [Benign]. Clinvar id is 307768.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00323 (492/152260) while in subpopulation SAS AF= 0.0423 (204/4822). AF 95% confidence interval is 0.0376. There are 12 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGP	NM_000900.5	c.*27T>G		3_prime_UTR_variant	4/4	ENST00000539261.6	NP_000891.2
MGP	NM_001190839.3	c.*27T>G		3_prime_UTR_variant	5/5		NP_001177768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGP	ENST00000539261.6	c.*27T>G		3_prime_UTR_variant	4/4	1	NM_000900.5	ENSP00000445907	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152142 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00796 AC: 1999 AN: 251006 Hom.: 53 AF XY: 0.00954 AC XY: 1294 AN XY: 135628

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0225

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.000926

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00396 AC: 5787 AN: 1461572 Hom.: 138 Cov.: 31 AF XY: 0.00504 AC XY: 3663 AN XY: 727116

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0275

Gnomad4 SAS exome AF: 0.0394

Gnomad4 FIN exome AF: 0.00992

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00547

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152260 Hom.: 12 Cov.: 31 AF XY: 0.00429 AC XY: 319 AN XY: 74440

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0211

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.0340 AC: 120 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Keutel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs80337043; hg19: chr12-15035046;