Genetic Variant NM_001113498.3:c.2519A>G (chr14-46874119-T-C) – 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.2519A>G(p.Gln840Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MDGA2
NM_001113498.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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=0.4056886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDGA2	NM_001113498.3 link	c.2519A>G	p.Gln840Arg	missense_variant	Exon 13 of 17	ENST00000399232.8	NP_001106970.4	Q7Z553-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDGA2	ENST00000399232.8 link	c.2519A>G	p.Gln840Arg	missense_variant	Exon 13 of 17	1	NM_001113498.3	ENSP00000382178.4		Q7Z553-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1400088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695016

African (AFR)

AF:

0.00

AC:

AN:

30156

American (AMR)

AF:

0.00

AC:

AN:

37344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24612

East Asian (EAS)

AF:

0.00

AC:

AN:

35722

South Asian (SAS)

AF:

0.00

AC:

AN:

74848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082518

Other (OTH)

AF:

0.00

AC:

AN:

57558

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

Oct 29, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2312A>G (p.Y771C) alteration is located in exon 11 (coding exon 11) of the MDGA2 gene. This alteration results from a A to G substitution at nucleotide position 2312, causing the tyrosine (Y) at amino acid position 771 to be replaced by a cysteine (C). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

.;.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.4

.;.;L

PhyloP100

7.7

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.15

Sift

Uncertain

0.024

D;D;.

Sift4G

Uncertain

0.035

.;D;.

Polyphen

0.93

.;.;P

Vest4

0.51

MutPred

0.54

.;.;Gain of catalytic residue at A774 (P = 0.0367);

MVP

0.38

MPC

1.4

ClinPred

0.91

GERP RS

5.5

Varity_R

0.21

gMVP

0.83

Mutation Taster

=170/130

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over