chrX-136874266-G-C

Variant names:

• chrX-136874266-G-C
• rs760262374
• NM_002139.4:c.1052C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002139.4(RBMX):​c.1052C>G​(p.Pro351Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000875 in 114,338 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000087 (0 hom., 0 hem., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RBMX NM_002139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99
• 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: Unknown, XL Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBMX	NM_002139.4	MANE Select	c.1052C>G	p.Pro351Arg	missense	Exon 9 of 9	NP_002130.2	P38159-1
	RBMX	NM_001164803.2		c.540+820C>G		intron	N/A	NP_001158275.1	P38159-3
	RBMX	NR_028476.2		n.1035C>G		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBMX	ENST00000320676.11	TSL:1 MANE Select	c.1052C>G	p.Pro351Arg	missense	Exon 9 of 9	ENSP00000359645.3	P38159-1
	RBMX	ENST00000562646.5	TSL:1	c.*794C>G		3_prime_UTR	Exon 8 of 8	ENSP00000457051.1	H3BT71
	RBMX	ENST00000568578.5	TSL:1	n.*1276C>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000457691.1	H3BR27

Frequencies

GnomAD3 genomes AF: 0.00000875 AC: 1 AN: 114338 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000375

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: 0.00 AC: 0 AN: 183284 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098073 Hom.: 0 Cov.: 80 AF XY: 0.00 AC XY: 0 AN XY: 363559

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842011

Other (OTH) AF: 0.00 AC: 0 AN: 46086

GnomAD4 genome AF: 0.00000875 AC: 1 AN: 114338 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 36458

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31661

American (AMR) AF: 0.00 AC: 0 AN: 10935

Ashkenazi Jewish (ASJ) AF: 0.000375 AC: 1 AN: 2666

East Asian (EAS) AF: 0.00 AC: 0 AN: 3642

South Asian (SAS) AF: 0.00 AC: 0 AN: 2923

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53602

Other (OTH) AF: 0.00 AC: 0 AN: 1550

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.39		Gain of MoRF binding (P = 6e-04)
MVP		0.94
MPC		2.3
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.70
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs760262374; hg19: chrX-135956425;