X-54810071-C-T

Position:

• chrX-54810071-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_177433.3(MAGED2):​c.395C>T​(p.Thr132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,411 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.463

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03987533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGED2	NM_177433.3	c.395C>T	p.Thr132Ile	missense_variant	3/13	ENST00000375068.6	NP_803182.1
MAGED2	NM_014599.6	c.395C>T	p.Thr132Ile	missense_variant	3/13		NP_055414.2
MAGED2	NM_201222.3	c.395C>T	p.Thr132Ile	missense_variant	3/13		NP_957516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED2	ENST00000375068.6	c.395C>T	p.Thr132Ile	missense_variant	3/13	1	NM_177433.3	ENSP00000364209	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095411 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 1 AN XY: 360989

Gnomad4 AFR exome AF: 0.00

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: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MAGED2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The MAGED2 c.395C>T variant is predicted to result in the amino acid substitution p.Thr132Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.0
DANN	Benign	0.69
DEOGEN2	Benign	0.045	T;T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.56	.;T;.;T;T;.;.;.
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.040	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
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	T
PROVEAN	Benign	-0.81	N;.;N;.;N;N;N;N
REVEL	Benign	0.012
Sift	Benign	0.20	T;.;T;.;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B;B;B;B
Vest4		0.051
MutPred		0.26		Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);
MVP		0.19
MPC		0.65
ClinPred		0.026	T
GERP RS		-3.6
Varity_R		0.044
gMVP		0.051

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs757108375; hg19: chrX-54836504;