Genetic Variant MAGEA4:p.Ser99Trp (chrX-151923960-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001011548.1(MAGEA4):c.296C>G(p.Ser99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S99L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 1 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07481772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1 link	c.296C>G	p.Ser99Trp	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.296C>G	p.Ser99Trp	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2		P43358

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112461

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34597

show subpopulations

Gnomad AFR

AF:

0.0000646

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182192

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

66730

show subpopulations

Gnomad AFR exome

AF:

0.000152

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097498

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362928

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000651

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112514

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34660

show subpopulations

Gnomad4 AFR

AF:

0.0000645

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>G (p.S99W) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a C to G substitution at nucleotide position 296, causing the serine (S) at amino acid position 99 to be replaced by a tryptophan (W). 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

0.15

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.4

DANN

Benign

0.96

DEOGEN2

Benign

0.11

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

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.24

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

M_CAP

Benign

0.00092

MetaRNN

Benign

0.075

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

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

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

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.9

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

REVEL

Benign

0.095

Sift

Uncertain

0.029

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

Sift4G

Benign

0.20

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

Polyphen

1.0

.;D;.;D;.;.;D;.;.;.;D;D;D;.

Vest4

0.32

MVP

0.18

MPC

0.0035

ClinPred

0.21

GERP RS

-4.9

Varity_R

0.060

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