X-149885084-G-A

Variant names:

Variant summary

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

The NM_005364.5(MAGEA8):c.812G>A(p.Arg271His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,210,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

MAGEA8
NM_005364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.69

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:45093): (MAGEA8 antisense RNA 1)

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=0.13545778).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5 link	c.812G>A	p.Arg271His	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2	P43361B2R9W4
MAGEA8	NM_001166400.2 link	c.812G>A	p.Arg271His	missense_variant	Exon 4 of 4		NP_001159872.1	P43361B2R9W4
MAGEA8	NM_001166401.2 link	c.812G>A	p.Arg271His	missense_variant	Exon 3 of 3		NP_001159873.1	P43361B2R9W4
MAGEA8-AS1	NR_102703.1 link	n.81-2586C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAGEA8	ENST00000286482.6 link	c.812G>A	p.Arg271His	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1	P43361
MAGEA8	ENST00000535454.5 link	c.812G>A	p.Arg271His	missense_variant	Exon 4 of 4	3		ENSP00000438293.1	P43361
MAGEA8	ENST00000542674.5 link	c.812G>A	p.Arg271His	missense_variant	Exon 3 of 3	3		ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112165

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34329

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

182926

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097853

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363235

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112165

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34329

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.812G>A (p.R271H) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the arginine (R) at amino acid position 271 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

0.084

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.2

DANN

Benign

0.96

DEOGEN2

Benign

0.0084

T;T;T

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.038

.;T;.

M_CAP

Benign

0.0010

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.027

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.018

B;B;B

Vest4

0.025

MutPred

0.36

Gain of glycosylation at S267 (P = 0.0919);Gain of glycosylation at S267 (P = 0.0919);Gain of glycosylation at S267 (P = 0.0919);

MVP

0.21

MPC

0.28

ClinPred

0.039

GERP RS

-0.86

Varity_R

0.065

gMVP

0.38

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