X-30250528-G-A

Position:

chrX-30250528-G-A

Variant summary

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

The ENST00000397548.4(MAGEB1):c.35G>A(p.Arg12His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,201,467 control chromosomes in the GnomAD database, including 2 homozygotes. There are 151 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 0.00019 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00041 ( 2 hom. 143 hem. )

Consequence

MAGEB1
ENST00000397548.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11241987).

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEB1	NM_177404.3 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	2/2	ENST00000397548.4	NP_796379.1	P43366
MAGEB1	NM_002363.5 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	4/4		NP_002354.2	P43366
MAGEB1	NM_177415.3 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	3/3		NP_803134.1	P43366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAGEB1	ENST00000397548.4 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	2/2	1	NM_177404.3	ENSP00000380681.2	P43366
MAGEB1	ENST00000378981.8 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	4/4	1		ENSP00000368264.3	P43366
MAGEB1	ENST00000397550.6 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	3/3	1		ENSP00000380683.1	P43366

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

112899

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

35059

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000560

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000337

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

166820

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

53120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000789

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000757

Gnomad SAS exome

AF:

0.0000681

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000413

AC:

450

AN:

1088514

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

143

AN XY:

355624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.0000192

Gnomad4 FIN exome

AF:

0.0000497

Gnomad4 NFE exome

AF:

0.000509

Gnomad4 OTH exome

AF:

0.000329

GnomAD4 genome

AF:

0.000186

AC:

AN:

112953

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

35123

show subpopulations

Gnomad4 AFR

AF:

0.0000321

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000561

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000337

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000351

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.35G>A (p.R12H) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a G to A substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a histidine (H). 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

0.30

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;T;T

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.84

.;T;.

M_CAP

Benign

0.056

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Benign

0.089

Sift

Benign

0.065

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.94

P;P;P

Vest4

0.20

MVP

0.28

MPC

0.26

ClinPred

0.19

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.23

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