NM_005676.5:c.1249-1G>C

Variant names:

• chrX-47181214-G-C
• rs1556778986
• NM_005676.5:c.1249-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005676.5(RBM10):​c.1249-1G>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 18)
• Consequence: RBM10 NM_005676.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

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]

RBM10 Gene-Disease associations (from GenCC):

• TARP syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.2, offset of 10, new splice context is: tgcccttcacgcctcccaAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005676.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM10	NM_005676.5	MANE Select	c.1249-1G>C		splice_acceptor intron	N/A	NP_005667.2
	RBM10	NM_001204468.2		c.1444-1G>C		splice_acceptor intron	N/A	NP_001191397.1	P98175-5
	RBM10	NM_001440861.1		c.1441-1G>C		splice_acceptor intron	N/A	NP_001427790.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBM10	ENST00000377604.8	TSL:1 MANE Select	c.1249-1G>C		splice_acceptor intron	N/A	ENSP00000366829.3	P98175-1
	RBM10	ENST00000329236.8	TSL:1	c.1444-1G>C		splice_acceptor intron	N/A	ENSP00000328848.8	P98175-5
	RBM10	ENST00000628161.2	TSL:1	c.1015-1G>C		splice_acceptor intron	N/A	ENSP00000486115.1	P98175-4

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	35
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.7
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 11
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs1556778986; hg19: chrX-47040613;