X-47169430-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005676.5(RBM10):​c.133C>A​(p.Pro45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,876 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

RBM10
NM_005676.5 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.597
Variant links:
Genes affected
RBM10 (HGNC:9896): (RNA binding motif protein 10) This gene encodes a nuclear protein that belongs to a family proteins that contain an RNA-binding motif. The encoded protein associates with hnRNP proteins and may be involved in regulating alternative splicing. Defects in this gene are the cause of the X-linked recessive disorder, TARP syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11718184).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBM10NM_005676.5 linkc.133C>A p.Pro45Thr missense_variant Exon 3 of 24 ENST00000377604.8 NP_005667.2 P98175-1A0A0S2Z4W4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBM10ENST00000377604.8 linkc.133C>A p.Pro45Thr missense_variant Exon 3 of 24 1 NM_005676.5 ENSP00000366829.3 P98175-1
RBM10ENST00000329236.8 linkc.328C>A p.Pro110Thr missense_variant Exon 3 of 24 1 ENSP00000328848.8 P98175-5
RBM10ENST00000628161.2 linkc.133C>A p.Pro45Thr missense_variant Exon 3 of 23 1 ENSP00000486115.1 P98175-4
RBM10ENST00000345781.10 linkc.133C>A p.Pro45Thr missense_variant Exon 3 of 23 2 ENSP00000329659.6 P98175-3

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.0000110
AC:
2
AN:
182281
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
66827
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000366
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000528
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097876
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 27, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Mar 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with RBM10-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant is present in population databases (rs782797549, gnomAD 0.005%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 45 of the RBM10 protein (p.Pro45Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;.;.;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.12
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;L;L;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.3
N;.;N;.
REVEL
Benign
0.080
Sift
Benign
0.037
D;.;T;.
Sift4G
Benign
0.50
T;T;T;T
Polyphen
0.95
P;D;D;.
Vest4
0.18
MutPred
0.25
Gain of phosphorylation at P45 (P = 0.0082);Gain of phosphorylation at P45 (P = 0.0082);Gain of phosphorylation at P45 (P = 0.0082);.;
MVP
0.37
MPC
1.7
ClinPred
0.21
T
GERP RS
4.7
Varity_R
0.23
gMVP
0.47

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: rs782797549; hg19: chrX-47028829; COSMIC: COSV61312875; API