X-152135595-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021048.5(MAGEA10):​c.26G>A​(p.Arg9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,137,846 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. R9C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.0000059 ( 0 hom. 3 hem. )

Consequence

MAGEA10
NM_021048.5 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0750
Variant links:
Genes affected
MAGEA10 (HGNC:6797): (MAGE family member A10) 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. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream melanoma antigen family A, 5 (MAGEA5) gene.[provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.045654953).
BS2
High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGEA10NM_021048.5 linkc.26G>A p.Arg9His missense_variant Exon 4 of 4 ENST00000370323.9 NP_066386.3 P43363B2RAE8
MAGEA10NM_001011543.3 linkc.26G>A p.Arg9His missense_variant Exon 5 of 5 NP_001011543.3 P43363B2RAE8
MAGEA10NM_001251828.2 linkc.26G>A p.Arg9His missense_variant Exon 5 of 5 NP_001238757.2 P43363B2RAE8
LOC100533997NM_001204811.3 linkc.-278+2880G>A intron_variant Intron 1 of 3 NP_001191740.1 P43359

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAGEA10ENST00000370323.9 linkc.26G>A p.Arg9His missense_variant Exon 4 of 4 1 NM_021048.5 ENSP00000359347.4 P43363

Frequencies

GnomAD3 genomes
AF:
0.0000445
AC:
5
AN:
112318
Hom.:
0
Cov.:
23
AF XY:
0.0000580
AC XY:
2
AN XY:
34466
show subpopulations
Gnomad AFR
AF:
0.0000971
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000935
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000585
AC:
6
AN:
1025528
Hom.:
0
Cov.:
31
AF XY:
0.00000920
AC XY:
3
AN XY:
326068
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:
0.0000238
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000495
Gnomad4 OTH exome
AF:
0.0000233
GnomAD4 genome
AF:
0.0000445
AC:
5
AN:
112318
Hom.:
0
Cov.:
23
AF XY:
0.0000580
AC XY:
2
AN XY:
34466
show subpopulations
Gnomad4 AFR
AF:
0.0000971
Gnomad4 AMR
AF:
0.0000935
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.00000862
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.26G>A (p.R9H) alteration is located in exon 5 (coding exon 1) of the MAGEA10 gene. This alteration results from a G to A substitution at nucleotide position 26, causing the arginine (R) at amino acid position 9 to be replaced by a histidine (H). 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
0.13
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
2.6
DANN
Benign
0.87
DEOGEN2
Benign
0.0018
T;T;T;T;.;.
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.44
.;T;T;T;T;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.046
T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.71
N;N;.;.;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.35
N;N;N;N;.;.
REVEL
Benign
0.030
Sift
Benign
0.50
T;T;T;T;.;.
Sift4G
Benign
0.57
T;T;.;.;T;.
Polyphen
0.13
B;B;.;.;.;.
Vest4
0.12
MutPred
0.24
Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);
MVP
0.39
MPC
0.39
ClinPred
0.098
T
GERP RS
-3.8
Varity_R
0.048
gMVP
0.12

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: rs760453323; hg19: chrX-151304067; API