Genetic Variant MDGA2:p.Val536Ile (chr14-47035224-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001113498.3(MDGA2):c.1606G>A(p.Val536Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MDGA2
NM_001113498.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Publications

0 publications found

Variant links:

Genes affected

MDGA2 (HGNC:19835): (MAM domain containing glycosylphosphatidylinositol anchor 2) Predicted to be involved in regulation of presynapse assembly; regulation of synaptic membrane adhesion; and spinal cord motor neuron differentiation. Predicted to act upstream of or within neuron migration and pattern specification process. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in GABA-ergic synapse and glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

MDGA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30550715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDGA2	NM_001113498.3 link	c.1606G>A	p.Val536Ile	missense_variant	Exon 8 of 17	ENST00000399232.8	NP_001106970.4	Q7Z553-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MDGA2	ENST00000399232.8 link	c.1606G>A	p.Val536Ile	missense_variant	Exon 8 of 17	1	NM_001113498.3	ENSP00000382178.4	Q7Z553-3
MDGA2	ENST00000357362.7 link	c.712G>A	p.Val238Ile	missense_variant	Exon 8 of 17	5		ENSP00000349925.3	Q7Z553-2
MDGA2	ENST00000554762.5 link	c.721G>A	p.Val241Ile	missense_variant	Exon 4 of 4	3		ENSP00000450827.1	H0YJ52
MDGA2	ENST00000557238.5 link	n.686G>A		non_coding_transcript_exon_variant	Exon 8 of 14	5		ENSP00000452593.1	G3V5Z1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1399G>A (p.G467R) alteration is located in exon 7 (coding exon 7) of the MDGA2 gene. This alteration results from a G to A substitution at nucleotide position 1399, causing the glycine (G) at amino acid position 467 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

.;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;T;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.8

.;.;L

PhyloP100

6.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.69

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.28

T;T;.

Sift4G

Benign

0.082

.;T;.

Polyphen

0.33

.;.;B

Vest4

0.36

MutPred

0.55

.;.;Gain of catalytic residue at K472 (P = 0);

MVP

0.66

MPC

0.21

ClinPred

0.65

GERP RS

5.5

Varity_R

0.076

gMVP

0.40

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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14-47035224-C-T

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