X-47169411-CATGGACTACCGTTCAT-C

Position:

• chrX-47169411-CATGGACTACCGTTCAT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005676.5(RBM10):​c.117_132del​(p.Met39IlefsTer90) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RBM10 NM_005676.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.98

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-47169411-CATGGACTACCGTTCAT-C is Pathogenic according to our data. Variant chrX-47169411-CATGGACTACCGTTCAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM10	NM_005676.5	c.117_132del	p.Met39IlefsTer90	frameshift_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.117_132del	p.Met39IlefsTer90	frameshift_variant	3/24	1	NM_005676.5	ENSP00000366829	A1
RBM10	ENST00000329236.8	c.312_327del	p.Met104IlefsTer90	frameshift_variant	3/24	1		ENSP00000328848	P3
RBM10	ENST00000628161.2	c.117_132del	p.Met39IlefsTer41	frameshift_variant	3/23	1		ENSP00000486115
RBM10	ENST00000345781.10	c.117_132del	p.Met39IlefsTer41	frameshift_variant	3/23	2		ENSP00000329659

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

TARP syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Apr 18, 2019

This frameshifting variant in exon 3 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.117_132del (p.Met39IlefsTer90) variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1934470534; hg19: chrX-47028810;