X-149884586-A-G

Position:

• chrX-149884586-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000286482.6(MAGEA8):​c.314A>G​(p.Glu105Gly) 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 1,097,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MAGEA8 ENST00000286482.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00800

Genes affected

MAGEA8 (HGNC:6806): (MAGE family member A8) 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. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2009]

MAGEA8-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26836127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.314A>G	p.Glu105Gly	missense_variant	3/3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.314A>G	p.Glu105Gly	missense_variant	4/4		NP_001159872.1
MAGEA8	NM_001166401.2	c.314A>G	p.Glu105Gly	missense_variant	3/3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-2088T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.314A>G	p.Glu105Gly	missense_variant	3/3	1	NM_005364.5	ENSP00000286482.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097180 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362572

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.: 24

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

Nov 19, 2022

The c.314A>G (p.E105G) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a A to G substitution at nucleotide position 314, causing the glutamic acid (E) at amino acid position 105 to be replaced by a glycine (G). 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	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T;T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.31	.;T;.
M_CAP	Benign	0.00077	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Benign	0.066
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.048
MutPred		0.34		Loss of catalytic residue at E105 (P = 0.0338);Loss of catalytic residue at E105 (P = 0.0338);Loss of catalytic residue at E105 (P = 0.0338);
MVP		0.50
MPC		0.85
ClinPred		0.96	D
GERP RS		-2.0
Varity_R		0.17
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-149013360;