Genetic Variant NM_000900.5:c.62-2A>T (chr12-14884247-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_000900.5(MGP):c.62-2A>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000788 in 1,268,442 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MGP
NM_000900.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGP	NM_000900.5 link	c.62-2A>T		splice_acceptor_variant, intron_variant	Intron 1 of 3	ENST00000539261.6	NP_000891.2	P08493-1A0A024RAX0
MGP	NM_001190839.3 link	c.137-2A>T		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>T		splice_acceptor_variant, intron_variant	Intron 1 of 3	1	NM_000900.5	ENSP00000445907.1		P08493-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134720

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.88e-7

AC:

AN:

1268442

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

632774

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:

28876

American (AMR)

AF:

0.00

AC:

AN:

38186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23212

East Asian (EAS)

AF:

0.00

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:

0.00

AC:

AN:

957548

Other (OTH)

AF:

0.0000190

AC:

AN:

52650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

134720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65942

African (AFR)

AF:

0.00

AC:

AN:

37328

American (AMR)

AF:

0.00

AC:

AN:

13220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3072

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

59188

Other (OTH)

AF:

0.00

AC:

AN:

1830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Benign

0.94

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.88

PhyloP100

4.0

GERP RS

5.2

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=3/97

disease causing

(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

0.23

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over