Genetic Variant MAGEA4:p.Gly192Cys (chrX-151924238-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001011548.1(MAGEA4):c.574G>T(p.Gly192Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,109 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.727

Variant links:

Genes affected

MAGEA4 (HGNC:6802): (MAGE family member A4) This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. Several variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

MAGEA4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22985595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1 link	c.574G>T	p.Gly192Cys	missense_variant	Exon 3 of 3	ENST00000276344.6	NP_001011548.1	P43358A0A024RC12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA4	ENST00000276344.6 link	c.574G>T	p.Gly192Cys	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2		P43358

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096109

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361621

show subpopulations

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:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574G>T (p.G192C) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a G to T substitution at nucleotide position 574, causing the glycine (G) at amino acid position 192 to be replaced by a cysteine (C). 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

0.21

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.043

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

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.039

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

M_CAP

Benign

0.0031

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;M;.;.;M;.;.;.;M;M;M;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.10

Sift

Benign

0.091

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

Sift4G

Uncertain

0.034

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

Polyphen

0.88

P;.;P;.;.;P;.;.;.;P;P;P;.

Vest4

0.13

MutPred

0.59

Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);Gain of catalytic residue at G192 (P = 0.0748);

MVP

0.12

MPC

0.0067

ClinPred

0.78

GERP RS

-1.6

Varity_R

0.37

gMVP

0.22

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over