X-151923950-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.286C>T​(p.Pro96Ser) 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 1,097,440 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P96P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

1
3
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.03
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1419566).
BS2
High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGEA4NM_001011548.1 linkc.286C>T p.Pro96Ser 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.286C>T p.Pro96Ser missense_variant Exon 3 of 3 2 NM_001011548.1 ENSP00000276344.2 P43358

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000549
AC:
1
AN:
182256
Hom.:
0
AF XY:
0.0000150
AC XY:
1
AN XY:
66804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000534
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097440
Hom.:
0
Cov.:
36
AF XY:
0.00000551
AC XY:
2
AN XY:
362884
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.286C>T (p.P96S) 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 286, causing the proline (P) at amino acid position 96 to be replaced by a serine (S). 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
0.094
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.91
CADD
Benign
13
DANN
Uncertain
0.97
DEOGEN2
Benign
0.011
T;T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.73
T;T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.14
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
.;M;.;M;.;.;M;.;.;.;M;M;M;.
PrimateAI
Benign
0.22
T
PROVEAN
Pathogenic
-4.5
D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Benign
0.045
Sift
Uncertain
0.0060
D;T;D;T;D;D;T;D;D;D;T;T;T;D
Sift4G
Benign
0.31
T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
1.0
.;D;.;D;.;.;D;.;.;.;D;D;D;.
Vest4
0.029, 0.030
MutPred
0.26
Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);
MVP
0.23
MPC
0.012
ClinPred
0.62
D
GERP RS
-3.4
Varity_R
0.11
gMVP
0.095

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: rs755313244; hg19: chrX-151092422; API