rs878854407

Positions:

• chrX-54814725-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_177433.3(MAGED2):​c.1336C>T​(p.Arg446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAGED2 NM_177433.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.33

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-54814725-C-T is Pathogenic according to our data. Variant chrX-54814725-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226034.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-54814725-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED2	NM_177433.3	c.1336C>T	p.Arg446Cys	missense_variant	11/13	ENST00000375068.6
MAGED2	NM_014599.6	c.1336C>T	p.Arg446Cys	missense_variant	11/13
MAGED2	NM_201222.3	c.1336C>T	p.Arg446Cys	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6	c.1336C>T	p.Arg446Cys	missense_variant	11/13	1	NM_177433.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097405 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362771

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bartter disease type 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 23, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32529326, 27120771, 29146702, 28973533, 34926352) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;.;.;.
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	4.0	H;.;H;.;H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.0	D;.;D;.;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.015	D;.;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D
Vest4		0.90
MutPred		0.94		Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);.;Loss of MoRF binding (P = 0.0088);
MVP		0.78
MPC		1.7
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854407; hg19: chrX-54841158;