X-136874287-C-T

Position:

• chrX-136874287-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002139.4(RBMX):​c.1031G>A​(p.Arg344Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RBMX NM_002139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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]

RBMX (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMX	NM_002139.4	c.1031G>A	p.Arg344Lys	missense_variant	9/9	ENST00000320676.11	NP_002130.2
RBMX	NM_001164803.2	c.540+799G>A		intron_variant			NP_001158275.1
RBMX	NR_028476.2	n.1014G>A		non_coding_transcript_exon_variant	8/8
RBMX	NR_028477.2	n.1221G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBMX	ENST00000320676.11	c.1031G>A	p.Arg344Lys	missense_variant	9/9	1	NM_002139.4	ENSP00000359645.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Shashi type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Jan 04, 2022

This patient is hemizygous for variant c.1031G>A in the RBMX gene on the X chromosome. This sequence variant is a single nucleotide substitution (G>A) that results in an arginine to lysine amino acid change at residue 344 of the RBMX protein. This amino acid falls within a tyrosine rich region which forms a domain necessary for R binding (PMID: 22832223). This is a novel variant that has not been reported to databases of clinically relevant variants and has not been observed in the medical literature, to our knowledge. Additiolly, this variant has not been observed in control population datasets (gnomAD database 0 of ~183,000 alleles). Bioinformatic tools predict that this variant would be damaging, and the Arg344 residue is highly conserved across the vertebrate species examined. Functiol studies examining the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;N
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.96	P;.
Vest4		0.45
MutPred		0.43		Gain of ubiquitination at R344 (P = 0.0077);.;
MVP		0.98
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135956446;