X-54810133-C-T

Position:

• chrX-54810133-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0390

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08269954).
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGED2	NM_177433.3	c.457C>T	p.Pro153Ser	missense_variant	3/13	ENST00000375068.6	NP_803182.1
MAGED2	NM_014599.6	c.457C>T	p.Pro153Ser	missense_variant	3/13		NP_055414.2
MAGED2	NM_201222.3	c.457C>T	p.Pro153Ser	missense_variant	3/13		NP_957516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6	c.457C>T	p.Pro153Ser	missense_variant	3/13	1	NM_177433.3	ENSP00000364209	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000124 AC: 2 AN: 161148 Hom.: 0 AF XY: 0.0000198 AC XY: 1 AN XY: 50536

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: 29 AN: 1083562 Hom.: 0 Cov.: 31 AF XY: 0.0000342 AC XY: 12 AN XY: 350810

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.: 22

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.041	T;T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.74	.;T;.;T;T;.;.;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
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	T
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	T
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

Other links and lift over

dbSNP: rs746508104; hg19: chrX-54836566; COSMIC: COSV54498889; COSMIC: COSV54498889;