X-54810125-C-A

Position:

chrX-54810125-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_177433.3(MAGED2):c.449C>A(p.Ala150Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,201,594 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 9 hem. )

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: -0.232

Variant links:

Genes affected

MAGED2 (HGNC:16353): (MAGE family member D2) This gene is a member of the MAGED gene family. The MAGED genes are clustered on chromosome Xp11. This gene is located in Xp11.2, a hot spot for X-linked intellectual disability (XLID). Mutations in this gene cause a form of transient antenatal Bartter's syndrome. This gene may also be involved in several types of cancer, including breast cancer and melanoma. The protein encoded by this gene is progressively recruited from the cytoplasm to the nucleoplasm during the interphase and after nucleolar stress and is thus thought to play a role in cell cycle regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

MAGED2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020515233).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAGED2	NM_177433.3 linkuse as main transcript	c.449C>A	p.Ala150Glu	missense_variant	3/13	ENST00000375068.6	NP_803182.1
MAGED2	NM_014599.6 linkuse as main transcript	c.449C>A	p.Ala150Glu	missense_variant	3/13		NP_055414.2
MAGED2	NM_201222.3 linkuse as main transcript	c.449C>A	p.Ala150Glu	missense_variant	3/13		NP_957516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6 linkuse as main transcript	c.449C>A	p.Ala150Glu	missense_variant	3/13	1	NM_177433.3	ENSP00000364209	P1	Q9UNF1-1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111565

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

33723

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000470

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

GnomAD3 exomes

AF:

0.000246

AC:

AN:

166652

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

55026

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00157

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000413

AC:

AN:

1090029

Hom.:

Cov.:

AF XY:

0.0000253

AC XY:

AN XY:

356197

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000656

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111565

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

33723

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000470

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2021

The c.449C>A (p.A150E) alteration is located in exon 3 (coding exon 2) of the MAGED2 gene. This alteration results from a C to A substitution at nucleotide position 449, causing the alanine (A) at amino acid position 150 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MAGED2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.6

DANN

Benign

0.93

DEOGEN2

Benign

0.040

T;T;T;T;T;T;T;T

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.63

.;T;.;T;T;.;.;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.021

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

N;.;N;.;N;N;.;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;.;N;.;N;N;N;N

REVEL

Benign

0.035

Sift

Uncertain

0.0070

D;.;D;.;D;D;D;D

Sift4G

Benign

0.72

T;T;T;T;T;T;T;T

Polyphen

0.65

P;B;P;.;P;P;B;P

Vest4

0.13

MutPred

0.13

Gain of solvent accessibility (P = 0.0456);.;Gain of solvent accessibility (P = 0.0456);.;Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);.;Gain of solvent accessibility (P = 0.0456);

MVP

0.25

MPC

0.70

ClinPred

0.029

GERP RS

0.32

Varity_R

0.27

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over