dbSNP rs1557371041: MAGEA8:p.Pro265Arg (chrX-149885066-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005364.5(MAGEA8):c.794C>G(p.Pro265Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,513 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

MAGEA8
NM_005364.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.702

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA8	NM_005364.5 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	ENST00000286482.6	NP_005355.2	P43361B2R9W4
MAGEA8	NM_001166400.2 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 4 of 4		NP_001159872.1	P43361B2R9W4
MAGEA8	NM_001166401.2 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3		NP_001159873.1	P43361B2R9W4
MAGEA8-AS1	NR_102703.1 link	n.81-2568G>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAGEA8	ENST00000286482.6 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	1	NM_005364.5	ENSP00000286482.1	P43361
MAGEA8	ENST00000535454.5 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 4 of 4	3		ENSP00000438293.1	P43361
MAGEA8	ENST00000542674.5 link	c.794C>G	p.Pro265Arg	missense_variant	Exon 3 of 3	3		ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097513

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362943

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.73

.;T;.

M_CAP

Benign

0.0014

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.6

H;H;H

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-8.3

D;D;D

REVEL

Benign

0.060

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.19

MutPred

0.83

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.17

MPC

0.85

ClinPred

1.0

GERP RS

1.0

Varity_R

0.71

gMVP

0.61

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over