chrX-154398527-G-A

Position:

• chrX-154398527-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_006013.5(RPL10):​c.8G>A​(p.Arg3His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: RPL10 NM_006013.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.01

Genes affected

RPL10 (HGNC:10298): (ribosomal protein L10) This gene encodes a ribosomal protein that is a component of the 60S ribosome subunit. The related protein in chicken can bind to c-Jun and can repress c-Jun-mediated transcriptional activation. Some studies have detected an association between variation in this gene and autism spectrum disorders, though others do not detect this relationship. There are multiple pseudogenes of this gene dispersed throughout the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154398527-G-A is Pathogenic according to our data. Variant chrX-154398527-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431945.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL10	NM_006013.5	c.8G>A	p.Arg3His	missense_variant	2/7	ENST00000369817.7	NP_006004.3
LOC124905228	XR_007068356.1	n.316C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL10	ENST00000369817.7	c.8G>A	p.Arg3His	missense_variant	2/7	5	NM_006013.5	ENSP00000358832	P1
	ENST00000624054.2	n.316C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 15, 2015

The R3H variant in the RPL10 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R3H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R3H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Functional studies suggest mutagenesis of the R3 residue reduces the interaction of RPL10 with it's chaperone protein, Sqt1 (Pausch et al., 2015). The R3H variant is a strong candidate for a pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;D;D;D;.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D;.;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.026	D;D;.;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T;T;D
Polyphen		0.63	.;.;.;.;.;P
Vest4		0.38
MutPred		0.41		Loss of methylation at R3 (P = 0.0393);Loss of methylation at R3 (P = 0.0393);Loss of methylation at R3 (P = 0.0393);Loss of methylation at R3 (P = 0.0393);Loss of methylation at R3 (P = 0.0393);Loss of methylation at R3 (P = 0.0393);
MVP		0.85
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557184925; hg19: chrX-153626868; COSMIC: COSV50010858; COSMIC: COSV50010858;