Genetic Variant MAGEB3:p.Pro131Ser (chrX-30236315-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002365.5(MAGEB3):c.391C>T(p.Pro131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,206,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

MAGEB3
NM_002365.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0180

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23962867).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB3	NM_002365.5 link	c.391C>T	p.Pro131Ser	missense_variant	Exon 5 of 5	ENST00000361644.4	NP_002356.2	O15480
MAGEB3	NM_001386865.1 link	c.391C>T	p.Pro131Ser	missense_variant	Exon 3 of 3		NP_001373794.1
MAGEB3	XM_011545513.3 link	c.391C>T	p.Pro131Ser	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.391C>T	p.Pro131Ser	missense_variant	Exon 5 of 5	2	NM_002365.5	ENSP00000355198.2		O15480
MAGEB3	ENST00000620842.1 link	c.391C>T	p.Pro131Ser	missense_variant	Exon 1 of 1	6		ENSP00000478513.1		O15480

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

112181

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34375

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00122

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:

0.00

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00000565

AC:

AN:

176968

Hom.:

AF XY:

0.0000160

AC XY:

AN XY:

62372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000382

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

AF:

0.00000640

AC:

AN:

1093857

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360143

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000175

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:

0.0000218

GnomAD4 genome

AF:

0.000152

AC:

AN:

112181

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34375

show subpopulations

Gnomad4 AFR

AF:

0.0000649

Gnomad4 AMR

AF:

0.00122

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00132

Bravo

AF:

0.000325

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391C>T (p.P131S) alteration is located in exon 5 (coding exon 1) of the MAGEB3 gene. This alteration results from a C to T substitution at nucleotide position 391, causing the proline (P) at amino acid position 131 to be replaced by a serine (S). 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

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

T;T

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.34

.;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-6.8

D;.

REVEL

Benign

0.071

Sift

Benign

0.083

T;.

Sift4G

Benign

0.084

T;T

Polyphen

0.95

P;P

Vest4

0.13

MutPred

0.68

Gain of phosphorylation at P131 (P = 0.0389);Gain of phosphorylation at P131 (P = 0.0389);

MVP

0.12

MPC

0.53

ClinPred

0.40

GERP RS

2.3

Varity_R

0.33

gMVP

0.44

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