X-136876650-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002139.4(RBMX):​c.394G>T​(p.Gly132Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,171,468 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 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 0.000055 ( 0 hom., 2 hem., cov: 21)
Exomes 𝑓: 0.00011 ( 0 hom. 25 hem. )

Consequence

RBMX
NM_002139.4 missense

Scores

1
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.903
Variant links:
Genes affected
RBMX (HGNC:9910): (RNA binding motif protein X-linked) This gene belongs to the RBMY gene family which includes candidate Y chromosome spermatogenesis genes. This gene, an active X chromosome homolog of the Y chromosome RBMY gene, is widely expressed whereas the RBMY gene evolved a male-specific function in spermatogenesis. Pseudogenes of this gene, found on chromosomes 1, 4, 9, 11, and 6, were likely derived by retrotransposition from the original gene. Alternatively spliced transcript variants encoding different isoforms have been identified. A snoRNA gene (SNORD61) is found in one of its introns. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3831419).
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBMXNM_002139.4 linkc.394G>T p.Gly132Cys missense_variant Exon 5 of 9 ENST00000320676.11 NP_002130.2 P38159-1
RBMXNM_001164803.2 linkc.217-1065G>T intron_variant Intron 3 of 7 NP_001158275.1 P38159-3
RBMXNR_028476.2 linkn.377G>T non_coding_transcript_exon_variant Exon 4 of 8
RBMXNR_028477.2 linkn.584G>T non_coding_transcript_exon_variant Exon 5 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBMXENST00000320676.11 linkc.394G>T p.Gly132Cys missense_variant Exon 5 of 9 1 NM_002139.4 ENSP00000359645.3 P38159-1

Frequencies

GnomAD3 genomes
AF:
0.0000546
AC:
6
AN:
109922
Hom.:
0
Cov.:
21
AF XY:
0.0000620
AC XY:
2
AN XY:
32238
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000175
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000949
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000449
AC:
7
AN:
155766
Hom.:
0
AF XY:
0.0000190
AC XY:
1
AN XY:
52714
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000134
Gnomad NFE exome
AF:
0.0000680
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000114
AC:
121
AN:
1061500
Hom.:
0
Cov.:
29
AF XY:
0.0000736
AC XY:
25
AN XY:
339654
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000505
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.0000901
GnomAD4 genome
AF:
0.0000546
AC:
6
AN:
109968
Hom.:
0
Cov.:
21
AF XY:
0.0000619
AC XY:
2
AN XY:
32294
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000175
Gnomad4 NFE
AF:
0.0000949
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000529
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
May 04, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.394G>T (p.G132C) alteration is located in exon 5 (coding exon 4) of the RBMX gene. This alteration results from a G to T substitution at nucleotide position 394, causing the glycine (G) at amino acid position 132 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
0.18
BayesDel_addAF
Benign
-0.063
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.34
T;.;T
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.75
T;T;D
M_CAP
Pathogenic
0.57
D
MetaRNN
Benign
0.38
T;T;T
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Benign
1.6
L;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.7
D;D;D
REVEL
Uncertain
0.47
Sift
Benign
0.030
D;D;D
Sift4G
Benign
0.061
T;D;D
Polyphen
0.25
B;.;.
Vest4
0.55
MutPred
0.39
Loss of MoRF binding (P = 0.0808);Loss of MoRF binding (P = 0.0808);.;
MVP
0.82
MPC
2.1
ClinPred
0.24
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.46
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs755202665; hg19: chrX-135958809; API