chrX-115190042-G-A

Position:

• chrX-115190042-G-A

Variant summary

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

The NM_001145346.2(RBMXL3):​c.601G>A​(p.Gly201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,153,864 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. 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: 𝑓 0.000027 (0 hom., 0 hem., cov: 26)
  • Exomes 𝑓: 0.000036 (0 hom. 6 hem.)
• Consequence: RBMXL3 NM_001145346.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.478

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02151084).
• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMXL3	NM_001145346.2	c.601G>A	p.Gly201Ser	missense_variant	1/1	ENST00000424776.5	NP_001138818.1
LRCH2	NM_020871.4	c.350-1672C>T		intron_variant		ENST00000317135.13	NP_065922.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBMXL3	ENST00000424776.5	c.601G>A	p.Gly201Ser	missense_variant	1/1	6	NM_001145346.2	ENSP00000417451.3
LRCH2	ENST00000317135.13	c.350-1672C>T		intron_variant		1	NM_020871.4	ENSP00000325091.8
LRCH2	ENST00000538422.2	c.350-1672C>T		intron_variant		1		ENSP00000439366.1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 3 AN: 112737 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 34965

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000571

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000189 AC: 18 AN: 95476 Hom.: 0 AF XY: 0.0000660 AC XY: 2 AN XY: 30312

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00156

Gnomad SAS exome AF: 0.0000825

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000838

Gnomad OTH exome AF: 0.000349

GnomAD4 exome AF: 0.0000355 AC: 37 AN: 1041127 Hom.: 0 Cov.: 35 AF XY: 0.0000178 AC XY: 6 AN XY: 336871

Gnomad4 AFR exome AF: 0.000203

Gnomad4 AMR exome AF: 0.0000369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0000206

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.0000684

GnomAD4 genome AF: 0.0000266 AC: 3 AN: 112737 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 34965

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000571

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000457 AC: 1

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

Sep 26, 2023

The c.601G>A (p.G201S) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a G to A substitution at nucleotide position 601, causing the glycine (G) at amino acid position 201 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	T
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.049
Sift	Benign	0.19	T
Sift4G	Benign	0.14	T
Polyphen		0.87	P
Vest4		0.014
MutPred		0.26		Gain of phosphorylation at G201 (P = 0.0104);
MVP		0.055
ClinPred		0.028	T
GERP RS		-0.72
Varity_R		0.055
gMVP		0.026

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: rs199745174; hg19: chrX-114424605; COSMIC: COSV57759091;