X-152135595-C-T

Variant names:

• chrX-152135595-C-T
• rs760453323
• NM_021048.5:c.26G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750

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]

LOC100533997 (HGNC:):

ACMG classification

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
MAGEA10	NM_021048.5	c.26G>A	p.Arg9His	missense_variant	Exon 4 of 4	ENST00000370323.9	NP_066386.3
MAGEA10	NM_001011543.3	c.26G>A	p.Arg9His	missense_variant	Exon 5 of 5		NP_001011543.3
MAGEA10	NM_001251828.2	c.26G>A	p.Arg9His	missense_variant	Exon 5 of 5		NP_001238757.2
LOC100533997	NM_001204811.3	c.-278+2880G>A		intron_variant	Intron 1 of 3		NP_001191740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA10	ENST00000370323.9	c.26G>A	p.Arg9His	missense_variant	Exon 4 of 4	1	NM_021048.5	ENSP00000359347.4

Frequencies

GnomAD3 genomes AF: 0.0000445 AC: 5 AN: 112318 Hom.: 0 Cov.: 23 AF XY: 0.0000580 AC XY: 2 AN XY: 34466

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

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

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

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

Other links and lift over

dbSNP: rs760453323; hg19: chrX-151304067;