chrX-149884410-C-G

Variant names:

• chrX-149884410-C-G
• rs782766025
• NM_005364.5:c.138C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005364.5(MAGEA8):​c.138C>G​(p.Ile46Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,432 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.428
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06776714).

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.138C>G	p.Ile46Met	missense	Exon 3 of 3	NP_005355.2
	MAGEA8	NM_001166400.2		c.138C>G	p.Ile46Met	missense	Exon 4 of 4	NP_001159872.1	P43361
	MAGEA8	NM_001166401.2		c.138C>G	p.Ile46Met	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.138C>G	p.Ile46Met	missense	Exon 3 of 3	ENSP00000286482.1	P43361
	MAGEA8	ENST00000535454.5	TSL:3	c.138C>G	p.Ile46Met	missense	Exon 4 of 4	ENSP00000438293.1	P43361
	MAGEA8	ENST00000542674.5	TSL:3	c.138C>G	p.Ile46Met	missense	Exon 3 of 3	ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112379 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180775 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112432 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34580

African (AFR) AF: 0.00 AC: 0 AN: 31045

American (AMR) AF: 0.00 AC: 0 AN: 10699

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53168

Other (OTH) AF: 0.00 AC: 0 AN: 1528

ExAC AF: 0.00000824 AC: 1

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	0.077
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	6.6
DANN	Benign	0.96
DEOGEN2	Benign	0.0054	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.43
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.072
Sift	Benign	0.42	T
Sift4G	Benign	0.25	T
Polyphen		0.95	P
Vest4		0.097
MutPred		0.14		Gain of glycosylation at T44 (P = 0.0885)
MVP		0.38
MPC		0.68
ClinPred		0.16	T
GERP RS		0.12
Varity_R		0.15
gMVP		0.061
Mutation Taster		=100/0	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

dbSNP: rs782766025; hg19: chrX-149013184;