X-30250855-G-C

Position:

chrX-30250855-G-C

Variant summary

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

The NM_177404.3(MAGEB1):c.362G>C(p.Arg121Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,210,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

MAGEB1
NM_177404.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.479

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=0.19140387).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAGEB1	NM_177404.3 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	2/2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	4/4		NP_002354.2
MAGEB1	NM_177415.3 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	3/3		NP_803134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAGEB1	ENST00000397548.4 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	2/2	1	NM_177404.3	ENSP00000380681	P1
MAGEB1	ENST00000378981.8 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	4/4	1		ENSP00000368264	P1
MAGEB1	ENST00000397550.6 linkuse as main transcript	c.362G>C	p.Arg121Pro	missense_variant	3/3	1		ENSP00000380683	P1

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112779

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34927

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183096

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67558

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

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:

0.00000456

AC:

AN:

1097303

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362675

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

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:

0.00

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112779

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34927

show subpopulations

Gnomad4 AFR

AF:

0.0000322

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

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

Sep 06, 2022

The c.362G>C (p.R121P) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a G to C substitution at nucleotide position 362, causing the arginine (R) at amino acid position 121 to be replaced by a proline (P). 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

Pathogenic

0.81

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.1

DANN

Benign

0.56

DEOGEN2

Benign

0.018

T;T;T

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.16

.;T;.

M_CAP

Benign

0.0037

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.038

B;B;B

Vest4

0.082

MutPred

0.49

Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);

MVP

0.54

MPC

0.066

ClinPred

0.032

GERP RS

-1.1

Varity_R

0.80

gMVP

0.70

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