X-72275731-C-A

Position:

• chrX-72275731-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000316084.10(RPS4X):​c.82-7G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,177,025 control chromosomes in the GnomAD database, including 2 homozygotes. There are 339 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., 37 hem., cov: 23)
  • Exomes 𝑓: 0.00088 (2 hom. 302 hem.)
• Consequence: RPS4X ENST00000316084.10 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001575
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.992

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-72275731-C-A is Benign according to our data. Variant chrX-72275731-C-A is described in ClinVar as [Benign]. Clinvar id is 756091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 37 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS4X	NM_001007.5	c.82-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000316084.10	NP_000998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS4X	ENST00000316084.10	c.82-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001007.5	ENSP00000362744	P1
PIN4	ENST00000439980.7	c.238-23251C>A		intron_variant, NMD_transcript_variant		4		ENSP00000394066
RPS4X	ENST00000373626.4	n.135-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3
RPS4X	ENST00000486733.2	n.72-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000847 AC: 94 AN: 110985 Hom.: 0 Cov.: 23 AF XY: 0.00111 AC XY: 37 AN XY: 33213

Gnomad AFR AF: 0.0000985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000965

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.00656

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000905

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00116 AC: 163 AN: 140049 Hom.: 1 AF XY: 0.000887 AC XY: 38 AN XY: 42841

Gnomad AFR exome AF: 0.000100

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000194

Gnomad FIN exome AF: 0.00710

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.000883 AC: 941 AN: 1065984 Hom.: 2 Cov.: 30 AF XY: 0.000886 AC XY: 302 AN XY: 340792

Gnomad4 AFR exome AF: 0.0000392

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000529

Gnomad4 EAS exome AF: 0.0000347

Gnomad4 SAS exome AF: 0.000254

Gnomad4 FIN exome AF: 0.00538

Gnomad4 NFE exome AF: 0.000803

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.000847 AC: 94 AN: 111041 Hom.: 0 Cov.: 23 AF XY: 0.00111 AC XY: 37 AN XY: 33279

Gnomad4 AFR AF: 0.0000983

Gnomad4 AMR AF: 0.0000964

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00117

Gnomad4 FIN AF: 0.00656

Gnomad4 NFE AF: 0.000905

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000473 Hom.: 2

Bravo AF: 0.000385

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.3
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.014
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: rs369740837; hg19: chrX-71495581;