X-115189977-G-C

Position:

• chrX-115189977-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145346.2(RBMXL3):​c.536G>C​(p.Arg179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: RBMXL3 NM_001145346.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0860

Genes affected

RBMXL3 (HGNC:26859): (RBMX like 3) Predicted to enable mRNA binding activity and snRNA binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be part of U12-type spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

LRCH2 (HGNC:29292): (leucine rich repeats and calponin homology domain containing 2) This gene encodes a member of the leucine-rich repeat and calponin homology domain-containing protein family. These family members contain multiple N-terminal leucine-rich repeats, in addition to a C-terminal calponin homology domain, a type of domain that mediates interactions with actin filaments. These proteins are conserved across animal species, and studies of a similar Drosophila protein indicate a function as a cytoskeletal scaffolding protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08151817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMXL3	NM_001145346.2	c.536G>C	p.Arg179Pro	missense_variant	1/1	ENST00000424776.5	NP_001138818.1
LRCH2	NM_020871.4	c.350-1607C>G		intron_variant		ENST00000317135.13	NP_065922.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBMXL3	ENST00000424776.5	c.536G>C	p.Arg179Pro	missense_variant	1/1	6	NM_001145346.2	ENSP00000417451.3
LRCH2	ENST00000317135.13	c.350-1607C>G		intron_variant		1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.350-1607C>G		intron_variant		1		ENSP00000439366.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.536G>C (p.R179P) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a G to C substitution at nucleotide position 536, causing the arginine (R) at amino acid position 179 to be replaced by a proline (P). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.0064	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.00095	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.75	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.023
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.051	T
Polyphen		0.23	B
Vest4		0.16
MutPred		0.44		Loss of MoRF binding (P = 7e-04);
MVP		0.030
ClinPred		0.18	T
GERP RS		0.72
Varity_R		0.21
gMVP		0.098

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-114424540;