X-149884429-G-T

Variant names:

• chrX-149884429-G-T
• rs181715136
• NM_005364.5:c.157G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005364.5(MAGEA8):​c.157G>T​(p.Val53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,209,915 control chromosomes in the GnomAD database, including 1 homozygotes. There are 68 hemizygotes 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (1 hom. 55 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010860175).
• BS2: High Hemizygotes in GnomAd4 at 13 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.157G>T	p.Val53Leu	missense	Exon 3 of 3	NP_005355.2
	MAGEA8	NM_001166400.2		c.157G>T	p.Val53Leu	missense	Exon 4 of 4	NP_001159872.1	P43361
	MAGEA8	NM_001166401.2		c.157G>T	p.Val53Leu	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.157G>T	p.Val53Leu	missense	Exon 3 of 3	ENSP00000286482.1	P43361
	MAGEA8	ENST00000535454.5	TSL:3	c.157G>T	p.Val53Leu	missense	Exon 4 of 4	ENSP00000438293.1	P43361
	MAGEA8	ENST00000542674.5	TSL:3	c.157G>T	p.Val53Leu	missense	Exon 3 of 3	ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 36 AN: 112157 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

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: 0.0000564

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.0000768 AC: 14 AN: 182180 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000183 AC: 201 AN: 1097704 Hom.: 1 Cov.: 30 AF XY: 0.000151 AC XY: 55 AN XY: 363064

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.000426 AC: 15 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54063

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.000207 AC: 174 AN: 841812

Other (OTH) AF: 0.000260 AC: 12 AN: 46068

GnomAD4 genome AF: 0.000321 AC: 36 AN: 112211 Hom.: 0 Cov.: 23 AF XY: 0.000378 AC XY: 13 AN XY: 34367

African (AFR) AF: 0.0000646 AC: 2 AN: 30941

American (AMR) AF: 0.00263 AC: 28 AN: 10662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6175

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53145

Other (OTH) AF: 0.00197 AC: 3 AN: 1526

Alfa AF: 0.000133 Hom.: 8

Bravo AF: 0.000423

ExAC AF: 0.0000741 AC: 9

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	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.4
DANN	Benign	0.73
DEOGEN2	Benign	0.0066	T
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.00068	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.072
Sift	Benign	0.25	T
Sift4G	Benign	0.42	T
Polyphen		0.040	B
Vest4		0.030
MutPred		0.11		Loss of glycosylation at S58 (P = 0.2391)
MVP		0.27
MPC		0.32
ClinPred		0.040	T
GERP RS		0.94
Varity_R		0.20
gMVP		0.11
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: rs181715136; hg19: chrX-149013203;