X-54810133-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_177433.3(MAGED2):c.457C>T(p.Pro153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,083,562 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: not found (cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 12 hem. )

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0390

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08269954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAGED2	NM_177433.3 linkuse as main transcript	c.457C>T	p.Pro153Ser	missense_variant	3/13	ENST00000375068.6
MAGED2	NM_014599.6 linkuse as main transcript	c.457C>T	p.Pro153Ser	missense_variant	3/13
MAGED2	NM_201222.3 linkuse as main transcript	c.457C>T	p.Pro153Ser	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6 linkuse as main transcript	c.457C>T	p.Pro153Ser	missense_variant	3/13	1	NM_177433.3	P1	Q9UNF1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

161148

Hom.:

AF XY:

0.0000198

AC XY:

AN XY:

50536

show subpopulations

Gnomad AFR exome

AF:

0.0000896

Gnomad AMR exome

AF:

0.00

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:

0.0000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000268

AC:

AN:

1083562

Hom.:

Cov.:

AF XY:

0.0000342

AC XY:

AN XY:

350810

show subpopulations

Gnomad4 AFR exome

AF:

0.0000385

Gnomad4 AMR exome

AF:

0.00

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:

0.0000336

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the MAGED2 protein (p.Pro153Ser). This variant is present in population databases (rs746508104, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MAGED2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.73

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.041

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

FATHMM_MKL

Benign

0.47

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.083

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

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

L;.;L;.;L;L;.;L

MutationTaster

Benign

0.95

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

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.60

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

REVEL

Benign

0.012

Sift

Benign

0.033

D;.;D;.;D;D;T;D

Sift4G

Benign

0.98

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

Polyphen

0.34

B;B;B;.;B;B;B;B

Vest4

0.075

MutPred

0.25

Gain of phosphorylation at P153 (P = 0.0033);.;Gain of phosphorylation at P153 (P = 0.0033);.;Gain of phosphorylation at P153 (P = 0.0033);Gain of phosphorylation at P153 (P = 0.0033);.;Gain of phosphorylation at P153 (P = 0.0033);

MVP

0.48

MPC

0.63

ClinPred

0.023

GERP RS

2.5

Varity_R

0.082

gMVP

0.18

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