X-151924031-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001011548.1(MAGEA4):​c.367C>T​(p.Arg123Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,210,757 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 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: 𝑓 0.000044 ( 0 hom., 4 hem., cov: 23)
Exomes 𝑓: 0.000033 ( 0 hom. 16 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07915035).
BS2
High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGEA4NM_001011548.1 linkc.367C>T p.Arg123Cys 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
MAGEA4ENST00000276344.6 linkc.367C>T p.Arg123Cys missense_variant Exon 3 of 3 2 NM_001011548.1 ENSP00000276344.2 P43358

Frequencies

GnomAD3 genomes
AF:
0.0000444
AC:
5
AN:
112641
Hom.:
0
Cov.:
23
AF XY:
0.000115
AC XY:
4
AN XY:
34791
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000280
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000280
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000161
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000982
AC:
18
AN:
183354
Hom.:
0
AF XY:
0.000118
AC XY:
8
AN XY:
67846
show subpopulations
Gnomad AFR exome
AF:
0.0000760
Gnomad AMR exome
AF:
0.000255
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000433
Gnomad SAS exome
AF:
0.0000525
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000367
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000328
AC:
36
AN:
1098116
Hom.:
0
Cov.:
36
AF XY:
0.0000440
AC XY:
16
AN XY:
363498
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000166
Gnomad4 SAS exome
AF:
0.000129
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000154
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000444
AC:
5
AN:
112641
Hom.:
0
Cov.:
23
AF XY:
0.000115
AC XY:
4
AN XY:
34791
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000280
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000280
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000161
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.367C>T (p.R123C) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a C to T substitution at nucleotide position 367, causing the arginine (R) at amino acid position 123 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
0.11
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.023
T;T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL
Benign
0.0052
N
LIST_S2
Benign
0.067
T;T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP
Benign
0.0096
T
MetaRNN
Benign
0.079
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.55
.;N;.;N;.;.;N;.;.;.;N;N;N;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.22
N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL
Benign
0.088
Sift
Benign
0.073
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.16
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.98
.;D;.;D;.;.;D;.;.;.;D;D;D;.
Vest4
0.036
MVP
0.082
MPC
0.0028
ClinPred
0.044
T
GERP RS
-0.54
Varity_R
0.093
gMVP
0.24

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.

Other links and lift over

dbSNP: rs143837393; hg19: chrX-151092503; COSMIC: COSV52340033; API