X-30250539-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_177404.3(MAGEB1):c.46C>T(p.Arg16Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,203,386 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. R16H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000022 ( 0 hom. 10 hem. )

Consequence

MAGEB1
NM_177404.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.121

Publications

2 publications found

Variant links:

Genes affected

MAGEB1 (HGNC:6808): (MAGE family member B1) This gene is a member of the MAGEB gene family. The members of this family have their entire coding sequences located in the last exon, and the encoded proteins show 50 to 68% sequence identity to each other. The promoters and first exons of the MAGEB genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. This gene is localized in the DSS (dosage-sensitive sex reversal) critical region, and expressed in testis and in a significant fraction of tumors of various histological types. This gene and other MAGEB members are clustered on chromosome Xp22-p21. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene, however, the full length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

MAGEB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11675346).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1	P43366
MAGEB1	NM_002363.5 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 4 of 4		NP_002354.2	P43366
MAGEB1	NM_177415.3 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 3 of 3		NP_803134.1	P43366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAGEB1	ENST00000397548.4 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2	P43366
MAGEB1	ENST00000378981.8 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 4 of 4	1		ENSP00000368264.3	P43366
MAGEB1	ENST00000397550.6 link	c.46C>T	p.Arg16Cys	missense_variant	Exon 3 of 3	1		ENSP00000380683.1	P43366

Frequencies

GnomAD3 genomes

AF:

0.0000620

AC:

AN:

112884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

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:

0.0000562

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000238

AC:

AN:

168234

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.000238

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:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1090502

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

356992

show subpopulations

African (AFR)

AF:

0.000191

AC:

AN:

26127

American (AMR)

AF:

0.00

AC:

AN:

34111

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18960

East Asian (EAS)

AF:

0.000133

AC:

AN:

30074

South Asian (SAS)

AF:

0.00

AC:

AN:

52342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40289

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

838748

Other (OTH)

AF:

0.0000219

AC:

AN:

45763

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000620

AC:

AN:

112884

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

35022

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

31060

American (AMR)

AF:

0.00

AC:

AN:

10788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3580

South Asian (SAS)

AF:

0.00

AC:

AN:

2743

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000562

AC:

AN:

53345

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.46C>T (p.R16C) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a C to T substitution at nucleotide position 46, causing the arginine (R) at amino acid position 16 to be replaced by a cysteine (C). 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

0.19

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

T;T;T

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.55

.;T;.

M_CAP

Benign

0.0040

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;M;M

PhyloP100

0.12

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Benign

0.042

Sift

Uncertain

0.021

D;D;D

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.83

P;P;P

Vest4

0.15

MVP

0.61

MPC

0.25

ClinPred

0.28

GERP RS

0.13

Varity_R

0.23

gMVP

0.15

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.

X-30250539-C-T

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