Genetic Variant MGP:c.62-2A>G (chr12-14884247-T-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_000900.5(MGP):c.62-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000237 in 1,268,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

MGP
NM_000900.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.05

Publications

1 publications found

Variant links:

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]

MGP links:

C12orf60 (HGNC:28726): (chromosome 12 open reading frame 60)

C12orf60 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10576923 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-14884247-T-C is Pathogenic according to our data. Variant chr12-14884247-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14342.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGP	NM_000900.5 link	c.62-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 3	ENST00000539261.6	NP_000891.2	P08493-1A0A024RAX0
MGP	NM_001190839.3 link	c.137-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 4		NP_001177768.1	P08493-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGP	ENST00000539261.6 link	c.62-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 3	1	NM_000900.5	ENSP00000445907.1		P08493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000529

AC:

AN:

189048

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000642

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000237

AC:

AN:

1268438

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

632772

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28878

American (AMR)

AF:

0.0000262

AC:

AN:

38186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23212

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37386

South Asian (SAS)

AF:

0.00

AC:

AN:

77340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5048

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

957544

Other (OTH)

AF:

0.00

AC:

AN:

52648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0561929), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Keutel syndrome

Pathogenic:1

Jan 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Benign

0.93

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.87

PhyloP100

4.0

GERP RS

5.2

PromoterAI

-0.0054

Neutral

(source)

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -15

DS_AL_spliceai

1.0

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over