Genetic Variant MAGEA4:p.Ser99Leu (chrX-151923960-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001011548.1(MAGEA4):c.296C>T(p.Ser99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,209,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S99W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 10 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.75

Publications

1 publications found

Variant links:

Genes affected

MAGEA4 (HGNC:6802): (MAGE family member A4) 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. Several variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

MAGEA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042612374).

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011548.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA4	NM_001011548.1	MANE Select	c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	NP_001011548.1	P43358
MAGEA4	NM_001011549.1		c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	NP_001011549.1	P43358
MAGEA4	NM_001011550.1		c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	NP_001011550.1	P43358

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA4	ENST00000276344.6	TSL:2 MANE Select	c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	ENSP00000276344.2	P43358
MAGEA4	ENST00000360243.6	TSL:1	c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	ENSP00000353379.2	P43358
MAGEA4	ENST00000370335.5	TSL:1	c.296C>T	p.Ser99Leu	missense	Exon 3 of 3	ENSP00000359360.1	P43358

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112461

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000274

AC:

AN:

182192

AF XY:

0.0000300

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000614

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097498

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

35169

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19320

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

53987

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40353

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

841872

Other (OTH)

AF:

0.0000217

AC:

AN:

46067

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112461

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34597

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30954

American (AMR)

AF:

0.00

AC:

AN:

10704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53249

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

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

0.094

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.16

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.032

FATHMM_MKL

Benign

0.0072

LIST_S2

Benign

0.14

M_CAP

Benign

0.00090

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-2.7

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.7

REVEL

Benign

0.026

Sift

Benign

1.0

Sift4G

Benign

0.73

Polyphen

0.10

Vest4

0.046

MutPred

0.26

Loss of phosphorylation at S99 (P = 0.0039)

MVP

0.093

MPC

0.0037

ClinPred

0.042

GERP RS

-4.9

Varity_R

0.034

gMVP

0.12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over