X-136876506-T-C

Variant names:

• chrX-136876506-T-C
• NM_002139.4:c.538A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002139.4(RBMX):​c.538A>G​(p.Arg180Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • 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: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBMX	NM_002139.4	c.538A>G	p.Arg180Gly	missense_variant	Exon 5 of 9	ENST00000320676.11	NP_002130.2
RBMX	NM_001164803.2	c.217-921A>G		intron_variant	Intron 3 of 7		NP_001158275.1
RBMX	NR_028476.2	n.521A>G		non_coding_transcript_exon_variant	Exon 4 of 8
RBMX	NR_028477.2	n.728A>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBMX	ENST00000320676.11	c.538A>G	p.Arg180Gly	missense_variant	Exon 5 of 9	1	NM_002139.4	ENSP00000359645.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1067584 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 345654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RBMX c.538A>G (p.Arg180Gly) results in a non-conservative amino acid change located in the RBM1CTR domain (IPR012604) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.538A>G in individuals affected with Syndromic X-Linked Intellectual Disability Shashi Type and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.87	P;.;.
Vest4		0.60
MutPred		0.55		Loss of methylation at R180 (P = 0.0042);Loss of methylation at R180 (P = 0.0042);.;
MVP		0.94
MPC		2.8
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.66
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135958665;