rs181515589

Variant names:

• chrX-136876663-A-G
• rs181515589
• NM_002139.4:c.389-8T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002139.4(RBMX):​c.389-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,152,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 6 hem., cov: 21)
  • Exomes 𝑓: 0.000014 (0 hom. 3 hem.)
• Consequence: RBMX NM_002139.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003871
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.351
• Publications: 0 publications found

Genes affected

RBMX (HGNC:9910): (RNA binding motif protein X-linked) This gene belongs to the RBMY gene family which includes candidate Y chromosome spermatogenesis genes. This gene, an active X chromosome homolog of the Y chromosome RBMY gene, is widely expressed whereas the RBMY gene evolved a male-specific function in spermatogenesis. Pseudogenes of this gene, found on chromosomes 1, 4, 9, 11, and 6, were likely derived by retrotransposition from the original gene. Alternatively spliced transcript variants encoding different isoforms have been identified. A snoRNA gene (SNORD61) is found in one of its introns. [provided by RefSeq, Sep 2009]

RBMX Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Shashi type

  Inheritance: XL, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Hemizygotes in GnomAd4 at 6 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002139.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBMX	NM_002139.4	MANE Select	c.389-8T>C		splice_region intron	N/A	NP_002130.2
	RBMX	NM_001164803.2		c.217-1078T>C		intron	N/A	NP_001158275.1
	RBMX	NR_028476.2		n.372-8T>C		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBMX	ENST00000320676.11	TSL:1 MANE Select	c.389-8T>C		splice_region intron	N/A	ENSP00000359645.3
	RBMX	ENST00000562646.5	TSL:1	c.389-8T>C		splice_region intron	N/A	ENSP00000457051.1
	RBMX	ENST00000568578.5	TSL:1	n.217-8T>C		splice_region intron	N/A	ENSP00000457691.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 13 AN: 110052 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000346 AC: 5 AN: 144472 AF XY: 0.0000208

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.0000598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 15 AN: 1042594 Hom.: 0 Cov.: 26 AF XY: 0.00000911 AC XY: 3 AN XY: 329302

African (AFR) AF: 0.000380 AC: 9 AN: 23672

American (AMR) AF: 0.0000415 AC: 1 AN: 24070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16850

East Asian (EAS) AF: 0.00 AC: 0 AN: 29397

South Asian (SAS) AF: 0.0000211 AC: 1 AN: 47391

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38869

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3890

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 814913

Other (OTH) AF: 0.0000919 AC: 4 AN: 43542

GnomAD4 genome AF: 0.000118 AC: 13 AN: 110107 Hom.: 0 Cov.: 21 AF XY: 0.000185 AC XY: 6 AN XY: 32359

African (AFR) AF: 0.000429 AC: 13 AN: 30320

American (AMR) AF: 0.00 AC: 0 AN: 10253

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3481

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5791

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52668

Other (OTH) AF: 0.00 AC: 0 AN: 1483

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000945

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Syndromic X-linked intellectual disability Shashi type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.69
PhyloP100		-0.35
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs181515589; hg19: chrX-135958822;