Genetic Variant MAGEA3:p.Ala28Val (chrX-152700915-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005362.4(MAGEA3):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 11 hem., cov: 18)

Exomes 𝑓: 0.0011 ( 2 hom. 261 hem. )

Failed GnomAD Quality Control

Consequence

MAGEA3
NM_005362.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0240

Variant links:

Genes affected

MAGEA3 (HGNC:6801): (MAGE family member A3) 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. [provided by RefSeq, Jul 2008]

MAGEA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060705453).

BS2

High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA3	NM_005362.4 link	c.83C>T	p.Ala28Val	missense_variant	Exon 3 of 3	ENST00000370278.4	NP_005353.1	P43357

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAGEA3	ENST00000370278.4 link	c.83C>T	p.Ala28Val	missense_variant	Exon 3 of 3	1	NM_005362.4	ENSP00000359301.3	P43357
MAGEA3	ENST00000598245.2 link	c.83C>T	p.Ala28Val	missense_variant	Exon 3 of 3	2		ENSP00000473093.1	P43357
MAGEA3	ENST00000417212.5 link	c.83C>T	p.Ala28Val	missense_variant	Exon 3 of 3	2		ENSP00000392758.1	E7EMU0

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

AN:

99088

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

AN XY:

23586

show subpopulations

Gnomad AFR

AF:

0.0000793

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:

0.000192

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000181

AC:

AN:

55311

Hom.:

AF XY:

0.0000637

AC XY:

AN XY:

15693

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000112

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00112

AC:

1010

AN:

903598

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

261

AN XY:

255292

show subpopulations

Gnomad4 AFR exome

AF:

0.0000952

Gnomad4 AMR exome

AF:

0.000205

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000699

Gnomad4 FIN exome

AF:

0.000111

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000716

AC:

AN:

99118

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

AN XY:

23628

show subpopulations

Gnomad4 AFR

AF:

0.0000792

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000192

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00110

Hom.:

ExAC

AF:

0.0000134

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83C>T (p.A28V) alteration is located in exon 3 (coding exon 1) of the MAGEA3 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.1

DANN

Benign

0.85

DEOGEN2

Benign

0.082

T;T;T

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.73

.;T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.4

N;N;.

Sift

Benign

0.15

T;T;.

Sift4G

Benign

0.22

T;T;T

Vest4

0.048

MutPred

0.29

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.63

ClinPred

0.066

GERP RS

-0.60

Varity_R

0.10

gMVP

0.15

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