X-54809804-C-T

Position:

chrX-54809804-C-T

Variant summary

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

The NM_177433.3(MAGED2):c.128C>T(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,201,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 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 0.00024 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 9 hem. )

Consequence

MAGED2
NM_177433.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.186

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:

MAGED2 (HGNC:):

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=0.028511912).

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGED2	NM_177433.3 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	3/13	ENST00000375068.6	NP_803182.1	Q9UNF1-1A0A024R9Y7
MAGED2	NM_014599.6 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	3/13		NP_055414.2	Q9UNF1-1A0A024R9Y7
MAGED2	NM_201222.3 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	3/13		NP_957516.1	Q9UNF1-1A0A024R9Y7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6 linkuse as main transcript	c.128C>T	p.Pro43Leu	missense_variant	3/13	1	NM_177433.3	ENSP00000364209.1		Q9UNF1-1

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

110746

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

32976

show subpopulations

Gnomad AFR

AF:

0.000692

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000843

AC:

AN:

166019

Hom.:

AF XY:

0.0000561

AC XY:

AN XY:

53499

show subpopulations

Gnomad AFR exome

AF:

0.000505

Gnomad AMR exome

AF:

0.000154

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:

0.0000416

Gnomad OTH exome

AF:

0.000238

GnomAD4 exome

AF:

0.0000284

AC:

AN:

1090945

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

357341

show subpopulations

Gnomad4 AFR exome

AF:

0.000533

Gnomad4 AMR exome

AF:

0.000204

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000249

Gnomad4 NFE exome

AF:

0.00000716

Gnomad4 OTH exome

AF:

0.0000654

GnomAD4 genome

AF:

0.000244

AC:

AN:

110801

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

AN XY:

33041

show subpopulations

Gnomad4 AFR

AF:

0.000691

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000908

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain: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

Nov 21, 2023

The c.128C>T (p.P43L) alteration is located in exon 3 (coding exon 2) of the MAGED2 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). 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

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.9

DANN

Benign

0.97

DEOGEN2

Benign

0.19

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

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.61

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

M_CAP

Benign

0.0047

MetaRNN

Benign

0.029

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

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

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.2

D;.;D;.;D;D;N;D

REVEL

Benign

0.026

Sift

Benign

0.076

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

Sift4G

Uncertain

0.0070

D;D;D;T;D;D;D;D

Polyphen

0.036

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

Vest4

0.14

MVP

0.19

MPC

0.62

ClinPred

0.0089

GERP RS

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.15

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