X-115189754-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001145346.2(RBMXL3):c.313T>C(p.Ser105Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,165,678 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 26)

Exomes 𝑓: 0.000010 ( 0 hom. 1 hem. )

Consequence

RBMXL3
NM_001145346.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.11

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0499098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBMXL3	NM_001145346.2 link	c.313T>C	p.Ser105Pro	missense_variant	Exon 1 of 1	ENST00000424776.5	NP_001138818.1	Q8N7X1
LRCH2	NM_020871.4 link	c.350-1384A>G		intron_variant	Intron 1 of 20	ENST00000317135.13	NP_065922.3	Q5VUJ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RBMXL3	ENST00000424776.5 link	c.313T>C	p.Ser105Pro	missense_variant	Exon 1 of 1	6	NM_001145346.2	ENSP00000417451.3	Q8N7X1
LRCH2	ENST00000317135.13 link	c.350-1384A>G		intron_variant	Intron 1 of 20	1	NM_020871.4	ENSP00000325091.8	Q5VUJ6-1
LRCH2	ENST00000538422.2 link	c.350-1384A>G		intron_variant	Intron 1 of 19	1		ENSP00000439366.1	Q5VUJ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

113032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000185

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

GnomAD2 exomes

AF:

0.0000180

AC:

AN:

111340

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000516

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000313

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1052646

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

344018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24909

American (AMR)

AF:

0.000359

AC:

AN:

27891

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18635

East Asian (EAS)

AF:

0.00

AC:

AN:

27116

South Asian (SAS)

AF:

0.00

AC:

AN:

49873

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36769

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819037

Other (OTH)

AF:

0.0000226

AC:

AN:

44326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000177

AC:

AN:

113032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31181

American (AMR)

AF:

0.000185

AC:

AN:

10818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3526

South Asian (SAS)

AF:

0.00

AC:

AN:

2792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53336

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000289

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.313T>C (p.S105P) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a T to C substitution at nucleotide position 313, causing the serine (S) at amino acid position 105 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

Benign

0.20

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.00099

FATHMM_MKL

Benign

0.00034

LIST_S2

Benign

0.19

M_CAP

Benign

0.0062

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.53

PhyloP100

-1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

0.89

REVEL

Benign

0.11

Sift

Benign

0.39

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.028

MutPred

0.21

Loss of phosphorylation at S105 (P = 0.0037);

MVP

0.067

ClinPred

0.015

GERP RS

-1.0

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.081

gMVP

0.098

Mutation Taster

=99/1

polymorphism

(source)

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

Loading publications...

X-115189754-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over