X-136876650-C-A

Variant names:

• chrX-136876650-C-A
• rs755202665
• NM_002139.4:c.394G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.903

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]

ACMG classification

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
RBMX	NM_002139.4	c.394G>T	p.Gly132Cys	missense_variant	Exon 5 of 9	ENST00000320676.11	NP_002130.2
RBMX	NM_001164803.2	c.217-1065G>T		intron_variant	Intron 3 of 7		NP_001158275.1
RBMX	NR_028476.2	n.377G>T		non_coding_transcript_exon_variant	Exon 4 of 8
RBMX	NR_028477.2	n.584G>T		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBMX	ENST00000320676.11	c.394G>T	p.Gly132Cys	missense_variant	Exon 5 of 9	1	NM_002139.4	ENSP00000359645.3

Frequencies

GnomAD3 genomes AF: 0.0000546 AC: 6 AN: 109922 Hom.: 0 Cov.: 21 AF XY: 0.0000620 AC XY: 2 AN XY: 32238

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

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

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

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

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

Other links and lift over

dbSNP: rs755202665; hg19: chrX-135958809;