rs1049897

Positions:

• chr12-14881587-T-A

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.*552A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 153,966 control chromosomes in the GnomAD database, including 10,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10698 hom., cov: 31)
  • Exomes 𝑓: 0.30 (121 hom.)
• Consequence: MGP NM_000900.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.668

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=-0.89).
• BP6: Variant 12-14881587-T-A is Benign according to our data. Variant chr12-14881587-T-A is described in ClinVar as [Benign]. Clinvar id is 307759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGP	NM_000900.5	c.*552A>T		3_prime_UTR_variant	4/4	ENST00000539261.6	NP_000891.2
MGP	NM_001190839.3	c.*552A>T		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.*552A>T		3_prime_UTR_variant	4/4	1	NM_000900.5	ENSP00000445907	P1
C12orf60	ENST00000527783.1	n.76-17582T>A		intron_variant, non_coding_transcript_variant		2
C12orf60	ENST00000533472.1	n.87-22420T>A		intron_variant, non_coding_transcript_variant		3
C12orf60	ENST00000648334.1	n.126-22420T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55760 AN: 151760 Hom.: 10684 Cov.: 31

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.0978

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.301 AC: 629 AN: 2088 Hom.: 121 Cov.: 0 AF XY: 0.293 AC XY: 321 AN XY: 1096

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.248

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.367 AC: 55798 AN: 151878 Hom.: 10698 Cov.: 31 AF XY: 0.363 AC XY: 26963 AN XY: 74222

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.0975

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.372

Alfa AF: 0.368 Hom.: 1573

Bravo AF: 0.372

Asia WGS AF: 0.252 AC: 877 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.77
DANN	Benign	0.66

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: rs1049897; hg19: chr12-15034521;