X-115189841-G-T

Variant summary

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

The ENST00000317135.13(LRCH2):​c.350-1471C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000943 in 1,166,293 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts 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: 26)
Exomes 𝑓: 0.0000095 ( 0 hom. 3 hem. )

Consequence

LRCH2
ENST00000317135.13 intron

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.550
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]
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]

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=0.034478843).
BS2
High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RBMXL3NM_001145346.2 linkuse as main transcriptc.400G>T p.Ala134Ser missense_variant 1/1 ENST00000424776.5 NP_001138818.1
LRCH2NM_020871.4 linkuse as main transcriptc.350-1471C>A intron_variant ENST00000317135.13 NP_065922.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RBMXL3ENST00000424776.5 linkuse as main transcriptc.400G>T p.Ala134Ser missense_variant 1/1 NM_001145346.2 ENSP00000417451 P1
LRCH2ENST00000317135.13 linkuse as main transcriptc.350-1471C>A intron_variant 1 NM_020871.4 ENSP00000325091 P2Q5VUJ6-1
LRCH2ENST00000538422.2 linkuse as main transcriptc.350-1471C>A intron_variant 1 ENSP00000439366 A2Q5VUJ6-2

Frequencies

GnomAD3 genomes
AF:
0.00000881
AC:
1
AN:
113557
Hom.:
0
Cov.:
26
AF XY:
0.00
AC XY:
0
AN XY:
35687
show subpopulations
Gnomad AFR
AF:
0.0000319
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:
0.0000473
AC:
5
AN:
105738
Hom.:
0
AF XY:
0.0000262
AC XY:
1
AN XY:
38222
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000207
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000321
GnomAD4 exome
AF:
0.00000950
AC:
10
AN:
1052736
Hom.:
0
Cov.:
33
AF XY:
0.00000871
AC XY:
3
AN XY:
344388
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000143
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000366
Gnomad4 OTH exome
AF:
0.0000451
GnomAD4 genome
AF:
0.00000881
AC:
1
AN:
113557
Hom.:
0
Cov.:
26
AF XY:
0.00
AC XY:
0
AN XY:
35687
show subpopulations
Gnomad4 AFR
AF:
0.0000319
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:
0.0000151

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 submitterclinical testingAmbry GeneticsOct 29, 2021The c.400G>T (p.A134S) alteration is located in exon 1 (coding exon 1) of the RBMXL3 gene. This alteration results from a G to T substitution at nucleotide position 400, causing the alanine (A) at amino acid position 134 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
0.16
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.91
CADD
Benign
2.0
DANN
Benign
0.76
DEOGEN2
Benign
0.0014
T
FATHMM_MKL
Benign
0.00084
N
LIST_S2
Benign
0.20
T
M_CAP
Benign
0.00087
T
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-0.28
N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
0.080
N
REVEL
Benign
0.011
Sift
Benign
0.23
T
Sift4G
Benign
0.70
T
Polyphen
0.11
B
Vest4
0.026
MutPred
0.30
Gain of glycosylation at A134 (P = 0.0118);
MVP
0.061
ClinPred
0.034
T
GERP RS
-1.2
Varity_R
0.078
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.

Other links and lift over

dbSNP: rs991973068; hg19: chrX-114424404; API