Variant X-149884410-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005364.5(MAGEA8):c.138C>G(p.Ile46Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 112,432 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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)

Consequence

MAGEA8
NM_005364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.428

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06776714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAGEA8	NM_005364.5 linkuse as main transcript	c.138C>G	p.Ile46Met	missense_variant	3/3	ENST00000286482.6	NP_005355.2
MAGEA8-AS1	NR_102703.1 linkuse as main transcript	n.81-1912G>C		intron_variant, non_coding_transcript_variant
MAGEA8	NM_001166400.2 linkuse as main transcript	c.138C>G	p.Ile46Met	missense_variant	4/4		NP_001159872.1
MAGEA8	NM_001166401.2 linkuse as main transcript	c.138C>G	p.Ile46Met	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.138C>G	p.Ile46Met	missense_variant	3/3	1	NM_005364.5	ENSP00000286482	P1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112379

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34517

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:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000553

AC:

AN:

180775

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65359

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:

0.0000534

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112432

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34580

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:

0.000369

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Mar 07, 2023

The c.138C>G (p.I46M) alteration is located in exon 4 (coding exon 1) of the MAGEA8 gene. This alteration results from a C to G substitution at nucleotide position 138, causing the isoleucine (I) at amino acid position 46 to be replaced by a methionine (M). 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

0.077

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-1.1

CADD

Benign

6.6

DANN

Benign

0.96

DEOGEN2

Benign

0.0054

T;T;T

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.11

.;T;.

M_CAP

Benign

0.00094

MetaRNN

Benign

0.068

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.072

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.95

P;P;P

Vest4

0.097

MutPred

0.14

Gain of glycosylation at T44 (P = 0.0885);Gain of glycosylation at T44 (P = 0.0885);Gain of glycosylation at T44 (P = 0.0885);

MVP

0.38

MPC

0.68

ClinPred

0.16

GERP RS

0.12

Varity_R

0.15

gMVP

0.061

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