chr12-14881800-A-G

Position:

• chr12-14881800-A-G

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.*339T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 293,392 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (31 hom.)
• Consequence: MGP NM_000900.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.104

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=-0.91).
• BP6: Variant 12-14881800-A-G is Benign according to our data. Variant chr12-14881800-A-G is described in ClinVar as [Benign]. Clinvar id is 307764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00317 (482/152266) while in subpopulation SAS AF= 0.0406 (196/4826). AF 95% confidence interval is 0.036. There are 10 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGP	NM_000900.5	c.*339T>C		3_prime_UTR_variant	4/4	ENST00000539261.6	NP_000891.2
MGP	NM_001190839.3	c.*339T>C		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.*339T>C		3_prime_UTR_variant	4/4	1	NM_000900.5	ENSP00000445907	P1
C12orf60	ENST00000527783.1	n.76-17369A>G		intron_variant, non_coding_transcript_variant		2
C12orf60	ENST00000533472.1	n.87-22207A>G		intron_variant, non_coding_transcript_variant		3
C12orf60	ENST00000648334.1	n.126-22207A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152148 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0209

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00821 AC: 1159 AN: 141126 Hom.: 31 Cov.: 0 AF XY: 0.0108 AC XY: 815 AN XY: 75726

Gnomad4 AFR exome AF: 0.000678

Gnomad4 AMR exome AF: 0.000464

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0249

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.00932

Gnomad4 NFE exome AF: 0.000758

Gnomad4 OTH exome AF: 0.00673

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152266 Hom.: 10 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74452

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0207

Gnomad4 SAS AF: 0.0406

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.0340 AC: 119 AN: 3478

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 13, 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	-0.91
CADD	Benign	0.61
DANN	Benign	0.51

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: rs150038879; hg19: chr12-15034734;