X-47169430-C-A

Variant names:

• chrX-47169430-C-A
• rs782797549
• NM_005676.5:c.133C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.597

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]

ACMG classification

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
RBM10	NM_005676.5	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 24	ENST00000377604.8	NP_005667.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBM10	ENST00000377604.8	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 24	1	NM_005676.5	ENSP00000366829.3
RBM10	ENST00000329236.8	c.328C>A	p.Pro110Thr	missense_variant	Exon 3 of 24	1		ENSP00000328848.8
RBM10	ENST00000628161.2	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 23	1		ENSP00000486115.1
RBM10	ENST00000345781.10	c.133C>A	p.Pro45Thr	missense_variant	Exon 3 of 23	2		ENSP00000329659.6

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

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

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

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

Other links and lift over

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