X-152134803-T-C

Position:

• chrX-152134803-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000370323.9(MAGEA10):​c.818A>G​(p.Gln273Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: MAGEA10 ENST00000370323.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.153

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061122477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEA10	NM_021048.5	c.818A>G	p.Gln273Arg	missense_variant	4/4	ENST00000370323.9	NP_066386.3
LOC100533997	NM_001204811.3	c.-278+3672A>G		intron_variant			NP_001191740.1
MAGEA10	NM_001011543.3	c.818A>G	p.Gln273Arg	missense_variant	5/5		NP_001011543.3
MAGEA10	NM_001251828.2	c.818A>G	p.Gln273Arg	missense_variant	5/5		NP_001238757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA10	ENST00000370323.9	c.818A>G	p.Gln273Arg	missense_variant	4/4	1	NM_021048.5	ENSP00000359347	P1
MAGEA10	ENST00000244096.7	c.818A>G	p.Gln273Arg	missense_variant	5/5	2		ENSP00000244096	P1
	ENST00000577437.1	n.469+760A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098224 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363578

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.818A>G (p.Q273R) alteration is located in exon 5 (coding exon 1) of the MAGEA10 gene. This alteration results from a A to G substitution at nucleotide position 818, causing the glutamine (Q) at amino acid position 273 to be replaced by an arginine (R). 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	0.080
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.89
DEOGEN2	Benign	0.0081	T;T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.054
Sift	Benign	0.72	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0060	B;B
Vest4		0.037
MutPred		0.58		Loss of ubiquitination at K269 (P = 0.0683);Loss of ubiquitination at K269 (P = 0.0683);
MVP		0.29
MPC		0.086
ClinPred		0.048	T
GERP RS		-0.026
Varity_R		0.16
gMVP		0.27

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: rs1484937319; hg19: chrX-151303275;