X-47147489-A-G

Position:

• chrX-47147489-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005676.5(RBM10):​c.8A>G​(p.Tyr3Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,098,035 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: RBM10 NM_005676.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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 2 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=0.3475635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM10	NM_005676.5	c.8A>G	p.Tyr3Cys	missense_variant	2/24	ENST00000377604.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM10	ENST00000377604.8	c.8A>G	p.Tyr3Cys	missense_variant	2/24	1	NM_005676.5	A1
RBM10	ENST00000329236.8	c.203A>G	p.Tyr68Cys	missense_variant	2/24	1		P3
RBM10	ENST00000628161.2	c.8A>G	p.Tyr3Cys	missense_variant	2/23	1
RBM10	ENST00000345781.10	c.8A>G	p.Tyr3Cys	missense_variant	2/23	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098035 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363391

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RBM10-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3 of the RBM10 protein (p.Tyr3Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.;.
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	0.74	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D;.;D;.
REVEL	Benign	0.18
Sift	Benign	0.034	D;.;T;.
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.94	P;D;D;.
Vest4		0.51
MutPred		0.33		Gain of catalytic residue at M1 (P = 2e-04);Gain of catalytic residue at M1 (P = 2e-04);Gain of catalytic residue at M1 (P = 2e-04);.;
MVP		0.70
MPC		1.7
ClinPred		0.86	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.62

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: rs1877750604; hg19: chrX-47006888;