X-149885083-C-T

Variant names:

• chrX-149885083-C-T
• rs781942405
• NM_005364.5:c.811C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005364.5(MAGEA8):​c.811C>T​(p.Arg271Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,209,896 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.70

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07178727).
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.811C>T	p.Arg271Cys	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.811C>T	p.Arg271Cys	missense_variant	Exon 4 of 4		NP_001159872.1
MAGEA8	NM_001166401.2	c.811C>T	p.Arg271Cys	missense_variant	Exon 3 of 3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-2585G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.811C>T	p.Arg271Cys	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1
MAGEA8	ENST00000535454.5	c.811C>T	p.Arg271Cys	missense_variant	Exon 4 of 4	3		ENSP00000438293.1
MAGEA8	ENST00000542674.5	c.811C>T	p.Arg271Cys	missense_variant	Exon 3 of 3	3		ENSP00000443776.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112057 Hom.: 0 Cov.: 23 AF XY: 0.0000877 AC XY: 3 AN XY: 34215

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 4 AN: 182846 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1097788 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112108 Hom.: 0 Cov.: 23 AF XY: 0.0000875 AC XY: 3 AN XY: 34276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000563

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.811C>T (p.R271C) 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 811, causing the arginine (R) at amino acid position 271 to be replaced by a cysteine (C). 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	0.079
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.6
DANN	Benign	0.95
DEOGEN2	Benign	0.020	T;T;T
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.046	.;T;.
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.24	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.093	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.082
MutPred		0.42		Loss of disorder (P = 0.0324);Loss of disorder (P = 0.0324);Loss of disorder (P = 0.0324);
MVP		0.099
MPC		0.30
ClinPred		0.042	T
GERP RS		0.024
Varity_R		0.084
gMVP		0.60

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: rs781942405; hg19: chrX-149013857;