X-151924199-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001011548.1(MAGEA4):​c.535C>G​(p.Leu179Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,210,098 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

2
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0620
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGEA4NM_001011548.1 linkc.535C>G p.Leu179Val 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.535C>G p.Leu179Val missense_variant Exon 3 of 3 2 NM_001011548.1 ENSP00000276344.2 P43358

Frequencies

GnomAD3 genomes
AF:
0.00000889
AC:
1
AN:
112511
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34653
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000652
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097587
Hom.:
0
Cov.:
33
AF XY:
0.00000276
AC XY:
1
AN XY:
362975
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000889
AC:
1
AN:
112511
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34653
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.000652
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.535C>G (p.L179V) 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 535, causing the leucine (L) at amino acid position 179 to be replaced by a valine (V). 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
0.17
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
9.8
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.56
T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP
Benign
0.0089
T
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Pathogenic
3.1
M;.;M;.;.;M;.;.;.;M;M;M;.
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
0.16
Sift
Uncertain
0.016
D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.096
B;.;B;.;.;B;.;.;.;B;B;B;.
Vest4
0.35
MutPred
0.76
Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP
0.32
MPC
0.0054
ClinPred
0.80
D
GERP RS
0.55
Varity_R
0.61
gMVP
0.48

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: rs1933595269; hg19: chrX-151092671; API