X-149884598-G-A

Variant names:

• chrX-149884598-G-A
• rs782570321
• NM_005364.5:c.326G>A

Variant summary

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

The NM_005364.5(MAGEA8):​c.326G>A​(p.Arg109Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000992 in 1,209,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 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: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.00011 (0 hom. 33 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.573

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:45093): (MAGEA8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045180947).
• BS2: High Hemizygotes in GnomAdExome4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.326G>A	p.Arg109Gln	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.326G>A	p.Arg109Gln	missense_variant	Exon 4 of 4		NP_001159872.1
MAGEA8	NM_001166401.2	c.326G>A	p.Arg109Gln	missense_variant	Exon 3 of 3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-2100C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.326G>A	p.Arg109Gln	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112367 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34529

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000166 AC: 3 AN: 181157 Hom.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65741

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000370

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 117 AN: 1096813 Hom.: 0 Cov.: 31 AF XY: 0.0000911 AC XY: 33 AN XY: 362243

Gnomad4 AFR exome AF: 0.0000379

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: 0.000132

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112367 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34529

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326G>A (p.R109Q) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a G to A substitution at nucleotide position 326, causing the arginine (R) at amino acid position 109 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.15
DANN	Benign	0.92
DEOGEN2	Benign	0.0071	T;T;T
FATHMM_MKL	Benign	0.00052	N
LIST_S2	Benign	0.073	.;T;.
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.71	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.031	B;B;B
Vest4		0.027
MutPred		0.32		Loss of phosphorylation at S106 (P = 0.1113);Loss of phosphorylation at S106 (P = 0.1113);Loss of phosphorylation at S106 (P = 0.1113);
MVP		0.37
MPC		0.25
ClinPred		0.025	T
GERP RS		-0.69
Varity_R		0.10
gMVP		0.11

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: rs782570321; hg19: chrX-149013372;