X-136875536-T-C

Position:

• chrX-136875536-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001164803.2(RBMX):​c.266A>G​(p.Asn89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,125 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. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: RBMX NM_001164803.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.245

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09967014).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMX	NM_002139.4	c.591A>G	p.Glu197Glu	synonymous_variant	6/9	ENST00000320676.11	NP_002130.2
RBMX	NM_001164803.2	c.266A>G	p.Asn89Ser	missense_variant	4/8		NP_001158275.1
RBMX	NR_028476.2	n.574A>G		non_coding_transcript_exon_variant	5/8
RBMX	NR_028477.2	n.781A>G		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBMX	ENST00000320676.11	c.591A>G	p.Glu197Glu	synonymous_variant	6/9	1	NM_002139.4	ENSP00000359645.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098125 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363487

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000151

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

Baylor Genetics

Feb 18, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.89
DANN	Benign	0.90
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.039
Sift	Benign	0.12	T
Sift4G	Benign	0.086	T
Vest4		0.12
MutPred		0.38		Gain of glycosylation at N89 (P = 0.0183);
MVP		0.54
ClinPred		0.067	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1261521581; hg19: chrX-135957695; COSMIC: COSV100284860; COSMIC: COSV100284860;