NM_177404.3:c.362G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 14/21 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. R121L) has been classified 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

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.479

Publications

3 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]

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=0.19140387).
BS2
High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGEB1NM_177404.3 linkc.362G>C p.Arg121Pro missense_variant Exon 2 of 2 ENST00000397548.4 NP_796379.1 P43366
MAGEB1NM_002363.5 linkc.362G>C p.Arg121Pro missense_variant Exon 4 of 4 NP_002354.2 P43366
MAGEB1NM_177415.3 linkc.362G>C p.Arg121Pro missense_variant Exon 3 of 3 NP_803134.1 P43366

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAGEB1ENST00000397548.4 linkc.362G>C p.Arg121Pro missense_variant Exon 2 of 2 1 NM_177404.3 ENSP00000380681.2 P43366
MAGEB1ENST00000378981.8 linkc.362G>C p.Arg121Pro missense_variant Exon 4 of 4 1 ENSP00000368264.3 P43366
MAGEB1ENST00000397550.6 linkc.362G>C p.Arg121Pro missense_variant Exon 3 of 3 1 ENSP00000380683.1 P43366

Frequencies

GnomAD3 genomes
AF:
0.00000887
AC:
1
AN:
112779
Hom.:
0
Cov.:
24
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
GnomAD2 exomes
AF:
0.0000164
AC:
3
AN:
183096
AF XY:
0.0000148
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000456
AC:
5
AN:
1097303
Hom.:
0
Cov.:
30
AF XY:
0.00000551
AC XY:
2
AN XY:
362675
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26386
American (AMR)
AF:
0.000142
AC:
5
AN:
35206
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19375
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30201
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54099
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40530
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4134
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
841308
Other (OTH)
AF:
0.00
AC:
0
AN:
46064
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000887
AC:
1
AN:
112779
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
34927
show subpopulations
African (AFR)
AF:
0.0000322
AC:
1
AN:
31057
American (AMR)
AF:
0.00
AC:
0
AN:
10733
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2659
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3585
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2684
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6254
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53351
Other (OTH)
AF:
0.00
AC:
0
AN:
1531
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
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
Sep 06, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
T
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
N
LIST_S2
Benign
0.16
.;T;.
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.6
L;L;L
PhyloP100
0.48
PrimateAI
Benign
0.28
T
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
T
GERP RS
-1.1
Varity_R
0.80
gMVP
0.70
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs776705490; hg19: chrX-30268972; API