X-72275682-G-A

Variant names:

• chrX-72275682-G-A
• rs747294461
• NM_001007.5:c.124C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001007.5(RPS4X):​c.124C>T​(p.Leu42Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 5 hem.)
  • Failed GnomAD Quality Control
• Consequence: RPS4X NM_001007.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• Publications: 0 publications found

Genes affected

RPS4X (HGNC:10424): (ribosomal protein S4 X-linked) Cytoplasmic ribosomes, organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes ribosomal protein S4, a component of the 40S subunit. Ribosomal protein S4 is the only ribosomal protein known to be encoded by more than one gene, namely this gene and ribosomal protein S4, Y-linked (RPS4Y). The 2 isoforms encoded by these genes are not identical, but are functionally equivalent. Ribosomal protein S4 belongs to the S4E family of ribosomal proteins. This gene is not subject to X-inactivation. It has been suggested that haploinsufficiency of the ribosomal protein S4 genes plays a role in Turner syndrome; however, this hypothesis is controversial. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007.5. 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
	RPS4X	NM_001007.5	MANE Select	c.124C>T	p.Leu42Phe	missense	Exon 3 of 7	NP_000998.1	B2R491

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS4X	ENST00000316084.10	TSL:1 MANE Select	c.124C>T	p.Leu42Phe	missense	Exon 3 of 7	ENSP00000362744.4	P62701
	RPS4X	ENST00000897477.1		c.124C>T	p.Leu42Phe	missense	Exon 3 of 7	ENSP00000567536.1
	RPS4X	ENST00000944636.1		c.124C>T	p.Leu42Phe	missense	Exon 3 of 7	ENSP00000614695.1

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 111037 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000379

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: 0.0000113 AC: 2 AN: 177759 AF XY: 0.0000319

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000639 AC: 7 AN: 1094901 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 5 AN XY: 360379

African (AFR) AF: 0.00 AC: 0 AN: 26337

American (AMR) AF: 0.00 AC: 0 AN: 35092

Ashkenazi Jewish (ASJ) AF: 0.000258 AC: 5 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30154

South Asian (SAS) AF: 0.00 AC: 0 AN: 53885

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839534

Other (OTH) AF: 0.0000435 AC: 2 AN: 45959

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000901 AC: 1 AN: 111037 Hom.: 0 Cov.: 23 AF XY: 0.0000301 AC XY: 1 AN XY: 33257

African (AFR) AF: 0.00 AC: 0 AN: 30473

American (AMR) AF: 0.00 AC: 0 AN: 10352

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2567

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53069

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.065	T
Polyphen		0.94	P
Vest4		0.79
MutPred		0.50		Loss of catalytic residue at L42 (P = 0.0024)
MVP		0.94
MPC		1.9
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.89
Mutation Taster		=69/31	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: rs747294461; hg19: chrX-71495532;