X-47169430-C-A

Position:

• chrX-47169430-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RBM10. . Gene score misZ 4.4623 (greater than the threshold 3.09). GenCC has associacion of gene with TARP syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11718184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM10	NM_005676.5	c.133C>A	p.Pro45Thr	missense_variant	3/24	ENST00000377604.8	NP_005667.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM10	ENST00000377604.8	c.133C>A	p.Pro45Thr	missense_variant	3/24	1	NM_005676.5	ENSP00000366829	A1
RBM10	ENST00000329236.8	c.328C>A	p.Pro110Thr	missense_variant	3/24	1		ENSP00000328848	P3
RBM10	ENST00000628161.2	c.133C>A	p.Pro45Thr	missense_variant	3/23	1		ENSP00000486115
RBM10	ENST00000345781.10	c.133C>A	p.Pro45Thr	missense_variant	3/23	2		ENSP00000329659

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.133C>A (p.P45T) alteration is located in exon 3 (coding exon 2) of the RBM10 gene. This alteration results from a C to A substitution at nucleotide position 133, causing the proline (P) at amino acid position 45 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2022

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 has not been reported in the literature in individuals affected with RBM10-related conditions. 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;.
MutationTaster	Benign	0.86	D;N;N
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;