rs1800801

Positions:

• chr12-14885854-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000900.5(MGP):​c.-63G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,431,672 control chromosomes in the GnomAD database, including 89,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8386 hom., cov: 32)
  • Exomes 𝑓: 0.35 (81104 hom.)
• Consequence: MGP NM_000900.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-14885854-C-T is Benign according to our data. Variant chr12-14885854-C-T is described in ClinVar as [Benign]. Clinvar id is 307776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGP	NM_000900.5	c.-63G>A		5_prime_UTR_variant	1/4	ENST00000539261.6	NP_000891.2
MGP	NM_001190839.3	c.-63G>A		5_prime_UTR_variant	1/5		NP_001177768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGP	ENST00000539261.6	c.-63G>A		5_prime_UTR_variant	1/4	1	NM_000900.5	ENSP00000445907	P1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49012 AN: 151828 Hom.: 8375 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.349 AC: 446929 AN: 1279726 Hom.: 81104 Cov.: 18 AF XY: 0.348 AC XY: 224853 AN XY: 645564

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.0890

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.323 AC: 49045 AN: 151946 Hom.: 8386 Cov.: 32 AF XY: 0.318 AC XY: 23589 AN XY: 74252

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.350

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.0878

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.327

Alfa AF: 0.361 Hom.: 16688

Bravo AF: 0.327

Asia WGS AF: 0.197 AC: 687 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	This variant is associated with the following publications: (PMID: 24281054, 11073842) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Keutel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	-0.78
CADD	Benign	5.7
DANN	Benign	0.65

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: rs1800801; hg19: chr12-15038788; COSMIC: COSV57454325; COSMIC: COSV57454325;