X-149885066-C-T

Variant names:

• chrX-149885066-C-T
• rs1557371041
• NM_005364.5:c.794C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005364.5(MAGEA8):​c.794C>T​(p.Pro265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,097,513 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 8 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.794C>T	p.Pro265Leu	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.794C>T	p.Pro265Leu	missense_variant	Exon 4 of 4		NP_001159872.1
MAGEA8	NM_001166401.2	c.794C>T	p.Pro265Leu	missense_variant	Exon 3 of 3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-2568G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.794C>T	p.Pro265Leu	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1
MAGEA8	ENST00000535454.5	c.794C>T	p.Pro265Leu	missense_variant	Exon 4 of 4	3		ENSP00000438293.1
MAGEA8	ENST00000542674.5	c.794C>T	p.Pro265Leu	missense_variant	Exon 3 of 3	3		ENSP00000443776.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000275 AC: 5 AN: 181951 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66485

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: 0.0000493

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1097513 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 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: 0.0000261

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.794C>T (p.P265L) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a C to T substitution at nucleotide position 794, causing the proline (P) at amino acid position 265 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T;T;T
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Uncertain	0.86	.;D;.
M_CAP	Benign	0.0012	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-9.3	D;D;D
REVEL	Benign	0.054
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.19
MutPred		0.82		Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);
MVP		0.12
MPC		0.83
ClinPred		0.98	D
GERP RS		1.0
Varity_R		0.51
gMVP		0.63

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: rs1557371041; hg19: chrX-149013840;