X-149884475-C-T

Variant names:

• chrX-149884475-C-T
• rs143905132
• NM_005364.5:c.203C>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.203C>T​(p.Ala68Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,209,474 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 316 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00078 (0 hom. 302 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.318

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=0.0813427).
• BS2: High Hemizygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5	c.203C>T	p.Ala68Val	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2
MAGEA8	NM_001166400.2	c.203C>T	p.Ala68Val	missense_variant	Exon 4 of 4		NP_001159872.1
MAGEA8	NM_001166401.2	c.203C>T	p.Ala68Val	missense_variant	Exon 3 of 3		NP_001159873.1
MAGEA8-AS1	NR_102703.1	n.81-1977G>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6	c.203C>T	p.Ala68Val	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1

Frequencies

GnomAD3 genomes AF: 0.000412 AC: 46 AN: 111770 Hom.: 0 Cov.: 24 AF XY: 0.000412 AC XY: 14 AN XY: 33944

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000565

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000660

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000475 AC: 87 AN: 183047 Hom.: 0 AF XY: 0.000519 AC XY: 35 AN XY: 67497

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000438

Gnomad NFE exome AF: 0.000882

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000784 AC: 861 AN: 1097704 Hom.: 0 Cov.: 30 AF XY: 0.000832 AC XY: 302 AN XY: 363062

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000395

Gnomad4 NFE exome AF: 0.000959

Gnomad4 OTH exome AF: 0.000499

GnomAD4 genome AF: 0.000412 AC: 46 AN: 111770 Hom.: 0 Cov.: 24 AF XY: 0.000412 AC XY: 14 AN XY: 33944

Gnomad4 AFR AF: 0.0000975

Gnomad4 AMR AF: 0.000565

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000328

Gnomad4 NFE AF: 0.000660

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000706 Hom.: 29

Bravo AF: 0.000521

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.00120

EpiControl AF: 0.00125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203C>T (p.A68V) 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 203, causing the alanine (A) at amino acid position 68 to be replaced by a valine (V). 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	0.094
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	9.4
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0087	T;T;T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.62	.;T;.
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.040
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.015
MVP		0.56
MPC		0.70
ClinPred		0.061	T
GERP RS		1.2
Varity_R		0.089
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143905132; hg19: chrX-149013249; COSMIC: COSV54063796; COSMIC: COSV54063796;