X-149884300-T-C

Position:

chrX-149884300-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005364.5(MAGEA8):c.28T>C(p.Tyr10His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,200,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000024 ( 0 hom. 6 hem. )

Consequence

MAGEA8
NM_005364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.97

Variant links:

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 links:

MAGEA8-AS1 (HGNC:):

MAGEA8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08503178).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAGEA8	NM_005364.5 linkuse as main transcript	c.28T>C	p.Tyr10His	missense_variant	3/3	ENST00000286482.6	NP_005355.2
MAGEA8-AS1	NR_102703.1 linkuse as main transcript	n.81-1802A>G		intron_variant, non_coding_transcript_variant
MAGEA8	NM_001166400.2 linkuse as main transcript	c.28T>C	p.Tyr10His	missense_variant	4/4		NP_001159872.1
MAGEA8	NM_001166401.2 linkuse as main transcript	c.28T>C	p.Tyr10His	missense_variant	3/3		NP_001159873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA8	ENST00000286482.6 linkuse as main transcript	c.28T>C	p.Tyr10His	missense_variant	3/3	1	NM_005364.5	ENSP00000286482	P1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34574

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

165833

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52459

show subpopulations

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:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1088265

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

355649

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000311

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34574

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.28T>C (p.Y10H) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a T to C substitution at nucleotide position 28, causing the tyrosine (Y) at amino acid position 10 to be replaced by a histidine (H). 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

-0.60

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.060

DANN

Benign

0.53

DEOGEN2

Benign

0.0016

T;T;T

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.15

.;T;.

M_CAP

Benign

0.00068

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.023

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.81

P;P;P

Vest4

0.033

MutPred

0.34

Loss of phosphorylation at Y10 (P = 0.0352);Loss of phosphorylation at Y10 (P = 0.0352);Loss of phosphorylation at Y10 (P = 0.0352);

MVP

0.15

MPC

0.49

ClinPred

0.099

GERP RS

-2.0

Varity_R

0.055

gMVP

0.094

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over