X-149885066-C-G

Variant names:

• chrX-149885066-C-G
• NM_005364.5:c.794C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005364.5(MAGEA8):​c.794C>G​(p.Pro265Arg) 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 1,097,513 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.702

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.794C>G	p.Pro265Arg	missense_variant	Exon 4 of 4		NP_001159872.1
MAGEA8	NM_001166401.2	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-2568G>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1
MAGEA8	ENST00000535454.5	c.794C>G	p.Pro265Arg	missense_variant	Exon 4 of 4	3		ENSP00000438293.1
MAGEA8	ENST00000542674.5	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	3		ENSP00000443776.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097513 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362943

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.73	.;T;.
M_CAP	Benign	0.0014	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Benign	0.060
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.19
MutPred		0.83		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.17
MPC		0.85
ClinPred		1.0	D
GERP RS		1.0
Varity_R		0.71
gMVP		0.61

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-149013840;