Genetic Variant MAGEB3:p.Ile90Thr (chrX-30236193-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_002365.5(MAGEB3):c.269T>C(p.Ile90Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,209,003 control chromosomes in the GnomAD database, including 1 homozygotes. There are 9 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 (★).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000024 ( 1 hom. 7 hem. )

Consequence

MAGEB3
NM_002365.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.61

Publications

2 publications found

Variant links:

Genes affected

MAGEB3 (HGNC:6810): (MAGE family member B3) This gene is a MAGE-B subfamily member of the MAGE gene family. MAGE family member proteins direct the expression of tumor antigens recognized on a human melanoma by autologous cytolytic T lymphocytes. There are two known clusters of MAGE genes on chromosome X. The members of the MAGE-A subfamily are located in the Xq28 region, while the members of the MAGE-B subfamily are clustered in the Xp21 region. [provided by RefSeq, Jul 2008]

MAGEB3 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=0.006364614).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB3	NM_002365.5 link	c.269T>C	p.Ile90Thr	missense_variant	Exon 5 of 5	ENST00000361644.4	NP_002356.2	O15480
MAGEB3	NM_001386865.1 link	c.269T>C	p.Ile90Thr	missense_variant	Exon 3 of 3		NP_001373794.1
MAGEB3	XM_011545513.3 link	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 4		XP_011543815.1	O15480

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEB3	ENST00000361644.4 link	c.269T>C	p.Ile90Thr	missense_variant	Exon 5 of 5	2	NM_002365.5	ENSP00000355198.2		O15480
MAGEB3	ENST00000620842.1 link	c.269T>C	p.Ile90Thr	missense_variant	Exon 1 of 1	6		ENSP00000478513.1		O15480

Frequencies

GnomAD3 genomes

AF:

0.0000896

AC:

AN:

111556

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:

0.00169

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000753

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000665

AC:

AN:

180430

AF XY:

0.0000307

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000293

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000623

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1097394

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362776

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26372

American (AMR)

AF:

0.00

AC:

AN:

35145

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.000331

AC:

AN:

30191

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53973

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40477

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

841693

Other (OTH)

AF:

0.000109

AC:

AN:

46057

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000896

AC:

AN:

111609

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

33783

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30716

American (AMR)

AF:

0.00

AC:

AN:

10582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00169

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2611

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

53097

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000943

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.269T>C (p.I90T) alteration is located in exon 5 (coding exon 1) of the MAGEB3 gene. This alteration results from a T to C substitution at nucleotide position 269, causing the isoleucine (I) at amino acid position 90 to be replaced by a threonine (T). 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

0.050

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0010

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.0044

T;T

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.11

.;T

M_CAP

Benign

0.0014

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.97

L;L

PhyloP100

-4.6

PrimateAI

Benign

0.28

PROVEAN

Benign

0.58

N;.

REVEL

Benign

0.013

Sift

Benign

0.60

T;.

Sift4G

Benign

0.58

T;T

Polyphen

0.0040

B;B

Vest4

0.021

MVP

0.043

MPC

0.15

ClinPred

0.048

GERP RS

-8.2

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.039

gMVP

0.032

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over