X-115189944-C-T

Position:

chrX-115189944-C-T

Variant summary

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

The NM_001145346.2(RBMXL3):c.503C>T(p.Ser168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000975 in 1,158,569 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., 2 hem., cov: 25)

Exomes 𝑓: 0.000099 ( 0 hom. 31 hem. )

Consequence

RBMXL3
NM_001145346.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0750

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=0.06495449).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBMXL3	NM_001145346.2 linkuse as main transcript	c.503C>T	p.Ser168Leu	missense_variant	1/1	ENST00000424776.5	NP_001138818.1	Q8N7X1
LRCH2	NM_020871.4 linkuse as main transcript	c.350-1574G>A		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.503C>T	p.Ser168Leu	missense_variant	1/1	6	NM_001145346.2	ENSP00000417451.3	Q8N7X1
LRCH2	ENST00000317135.13 linkuse as main transcript	c.350-1574G>A		intron_variant		1	NM_020871.4	ENSP00000325091.8	Q5VUJ6-1
LRCH2	ENST00000538422.2 linkuse as main transcript	c.350-1574G>A		intron_variant		1		ENSP00000439366.1	Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000881

AC:

AN:

113487

Hom.:

Cov.:

AF XY:

0.0000561

AC XY:

AN XY:

35653

show subpopulations

Gnomad AFR

AF:

0.0000638

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:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.000647

GnomAD3 exomes

AF:

0.000111

AC:

AN:

98995

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

32651

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000737

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000684

GnomAD4 exome

AF:

0.0000986

AC:

103

AN:

1045082

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

339034

show subpopulations

Gnomad4 AFR exome

AF:

0.000323

Gnomad4 AMR exome

AF:

0.0000364

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000222

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000944

Gnomad4 NFE exome

AF:

0.0000478

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.0000881

AC:

AN:

113487

Hom.:

Cov.:

AF XY:

0.0000561

AC XY:

AN XY:

35653

show subpopulations

Gnomad4 AFR

AF:

0.0000638

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.000647

Bravo

AF:

0.0000982

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

Jan 09, 2024

The c.503C>T (p.S168L) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a C to T substitution at nucleotide position 503, causing the serine (S) at amino acid position 168 to be replaced by a leucine (L). 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

0.32

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.038

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.60

M_CAP

Benign

0.00098

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.10

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.98

Vest4

0.075

MutPred

0.30

Gain of stability (P = 0.0167);

MVP

0.030

ClinPred

0.077

GERP RS

1.4

Varity_R

0.079

gMVP

0.058

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