Genetic Variant MAGEA3:p.Ile209Met (chrX-152701459-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005362.4(MAGEA3):c.627C>G(p.Ile209Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,702 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. Synonymous variant affecting the same amino acid position (i.e. I209I) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

MAGEA3
NM_005362.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.320

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005362.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA3	NM_005362.4	MANE Select	c.627C>G	p.Ile209Met	missense	Exon 3 of 3	NP_005353.1	P43357

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA3	ENST00000370278.4	TSL:1 MANE Select	c.627C>G	p.Ile209Met	missense	Exon 3 of 3	ENSP00000359301.3	P43357
MAGEA3	ENST00000598245.2	TSL:2	c.627C>G	p.Ile209Met	missense	Exon 3 of 3	ENSP00000473093.1	P43357
MAGEA3	ENST00000933889.1		c.627C>G	p.Ile209Met	missense	Exon 3 of 3	ENSP00000603948.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26384

American (AMR)

AF:

0.00

AC:

AN:

35155

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19354

East Asian (EAS)

AF:

0.00

AC:

AN:

30159

South Asian (SAS)

AF:

0.00

AC:

AN:

54010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841152

Other (OTH)

AF:

0.00

AC:

AN:

46046

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

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.56

M_CAP

Benign

0.0022

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.0

PhyloP100

-0.32

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.35

MutPred

0.84

Loss of catalytic residue at I209 (P = 0.0909)

MVP

0.50

ClinPred

0.97

GERP RS

-0.54

Varity_R

0.80

gMVP

0.80

Mutation Taster

=99/1

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