X-130412451-G-A

Variant names:

• chrX-130412451-G-A
• rs1233273285
• NM_016024.4:c.572G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016024.4(RBMX2):​c.572G>A​(p.Arg191His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,097,983 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: RBMX2 NM_016024.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.304

Genes affected

RBMX2 (HGNC:24282): (RNA binding motif protein X-linked 2) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053551614).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBMX2	NM_016024.4	c.572G>A	p.Arg191His	missense_variant	Exon 6 of 6	ENST00000305536.11	NP_057108.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBMX2	ENST00000305536.11	c.572G>A	p.Arg191His	missense_variant	Exon 6 of 6	1	NM_016024.4	ENSP00000339090.4
RBMX2	ENST00000487274.1	n.*56G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181324 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000738

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: 0.00000455 AC: 5 AN: 1097983 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 3 AN XY: 363429

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572G>A (p.R191H) alteration is located in exon 6 (coding exon 6) of the RBMX2 gene. This alteration results from a G to A substitution at nucleotide position 572, causing the arginine (R) at amino acid position 191 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	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.7
DANN	Benign	0.31
DEOGEN2	Benign	0.090	T;.
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.11	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.080	N;.
REVEL	Benign	0.035
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.14	T;.
Polyphen		0.0070	B;.
Vest4		0.043
MutPred		0.31		Loss of MoRF binding (P = 0.0219);Loss of MoRF binding (P = 0.0219);
MVP		0.093
MPC		0.45
ClinPred		0.27	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.082

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

Other links and lift over

dbSNP: rs1233273285; hg19: chrX-129546425; COSMIC: COSV59729730; COSMIC: COSV59729730;