X-115190075-A-G

Position:

chrX-115190075-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001145346.2(RBMXL3):c.634A>G(p.Ser212Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,153,102 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 0.0000088 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

RBMXL3
NM_001145346.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18

Variant links:

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]

RBMXL3 links:

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]

LRCH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050813913).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMXL3	NM_001145346.2 linkuse as main transcript	c.634A>G	p.Ser212Gly	missense_variant	1/1	ENST00000424776.5	NP_001138818.1	Q8N7X1
LRCH2	NM_020871.4 linkuse as main transcript	c.350-1705T>C		intron_variant		ENST00000317135.13	NP_065922.3	Q5VUJ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RBMXL3	ENST00000424776.5 linkuse as main transcript	c.634A>G	p.Ser212Gly	missense_variant	1/1	6	NM_001145346.2	ENSP00000417451.3	Q8N7X1
LRCH2	ENST00000317135.13 linkuse as main transcript	c.350-1705T>C		intron_variant		1	NM_020871.4	ENSP00000325091.8	Q5VUJ6-1
LRCH2	ENST00000538422.2 linkuse as main transcript	c.350-1705T>C		intron_variant		1		ENSP00000439366.1	Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35352

show subpopulations

Gnomad AFR

AF:

0.0000320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

95999

Hom.:

AF XY:

0.0000670

AC XY:

AN XY:

29833

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1039906

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

334428

show subpopulations

Gnomad4 AFR exome

AF:

0.0000405

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000268

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000228

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35352

show subpopulations

Gnomad4 AFR

AF:

0.0000320

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000180

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.634A>G (p.S212G) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a A to G substitution at nucleotide position 634, causing the serine (S) at amino acid position 212 to be replaced by a glycine (G). 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

0.26

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.94

CADD

Benign

9.9

DANN

Benign

0.61

DEOGEN2

Benign

0.0045

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.29

M_CAP

Benign

0.00071

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.56

REVEL

Benign

0.054

Sift

Uncertain

0.0070

Sift4G

Benign

0.14

Polyphen

0.62

Vest4

0.0080

MutPred

0.21

Loss of phosphorylation at S212 (P = 0.0089);

MVP

0.055

ClinPred

0.045

GERP RS

0.15

Varity_R

0.054

gMVP

0.0095

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over