dbSNP rs181715136: MAGEA8:p.Val53Leu (chrX-149884429-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005364.5(MAGEA8):c.157G>C(p.Val53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,705 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

MAGEA8
NM_005364.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066681385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005364.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA8	NM_005364.5	MANE Select	c.157G>C	p.Val53Leu	missense	Exon 3 of 3	NP_005355.2
MAGEA8	NM_001166400.2		c.157G>C	p.Val53Leu	missense	Exon 4 of 4	NP_001159872.1	P43361
MAGEA8	NM_001166401.2		c.157G>C	p.Val53Leu	missense	Exon 3 of 3	NP_001159873.1	P43361

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA8	ENST00000286482.6	TSL:1 MANE Select	c.157G>C	p.Val53Leu	missense	Exon 3 of 3	ENSP00000286482.1	P43361
MAGEA8	ENST00000535454.5	TSL:3	c.157G>C	p.Val53Leu	missense	Exon 4 of 4	ENSP00000438293.1	P43361
MAGEA8	ENST00000542674.5	TSL:3	c.157G>C	p.Val53Leu	missense	Exon 3 of 3	ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097705

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363065

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26390

American (AMR)

AF:

0.00

AC:

AN:

35182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40509

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841812

Other (OTH)

AF:

0.00

AC:

AN:

46068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.98

CADD

Benign

3.5

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0066

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.32

M_CAP

Benign

0.00068

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

1.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

REVEL

Benign

0.072

Sift

Benign

0.25

Sift4G

Benign

0.42

Polyphen

0.040

Vest4

0.030

MutPred

0.11

Loss of glycosylation at S58 (P = 0.2391)

MVP

0.27

MPC

0.32

ClinPred

0.20

GERP RS

0.94

Varity_R

0.20

gMVP

0.11

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over