X-149885036-A-G

Variant names:

• chrX-149885036-A-G
• NM_005364.5:c.764A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005364.5(MAGEA8):​c.764A>G​(p.Gln255Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,096,137 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.695
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21079853).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA8	NM_005364.5	MANE Select	c.764A>G	p.Gln255Arg	missense	Exon 3 of 3	NP_005355.2
	MAGEA8	NM_001166400.2		c.764A>G	p.Gln255Arg	missense	Exon 4 of 4	NP_001159872.1	P43361
	MAGEA8	NM_001166401.2		c.764A>G	p.Gln255Arg	missense	Exon 3 of 3	NP_001159873.1	P43361

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA8	ENST00000286482.6	TSL:1 MANE Select	c.764A>G	p.Gln255Arg	missense	Exon 3 of 3	ENSP00000286482.1	P43361
	MAGEA8	ENST00000535454.5	TSL:3	c.764A>G	p.Gln255Arg	missense	Exon 4 of 4	ENSP00000438293.1	P43361
	MAGEA8	ENST00000542674.5	TSL:3	c.764A>G	p.Gln255Arg	missense	Exon 3 of 3	ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096137 Hom.: 0 Cov.: 31 AF XY: 0.00000829 AC XY: 3 AN XY: 361787

African (AFR) AF: 0.0000379 AC: 1 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35131

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19176

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 53644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00000951 AC: 8 AN: 841055

Other (OTH) AF: 0.00 AC: 0 AN: 46014

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.00065	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.69
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.057
Sift	Benign	0.068	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.067
MutPred		0.50		Gain of MoRF binding (P = 0.0188)
MVP		0.38
MPC		0.31
ClinPred		0.35	T
GERP RS		-0.71
Varity_R		0.16
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chrX-149013810;