rs7899453

Positions:

• chr10-78040201-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033022.4(RPS24):​c.391-3C>A 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 0.0127 in 1,613,192 control chromosomes in the GnomAD database, including 1,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (1012 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (919 hom.)
• Consequence: RPS24 NM_033022.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.64

Genes affected

RPS24 (HGNC:10411): (ribosomal protein S24) Ribosomes, the 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 a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S24E family of ribosomal proteins. It is located in the cytoplasm. Multiple transcript variants encoding different isoforms have been found for this gene. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Mutations in this gene result in Diamond-Blackfan anemia. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013203025).
• BP6: Variant 10-78040201-C-A is Benign according to our data. Variant chr10-78040201-C-A is described in ClinVar as [Benign]. Clinvar id is 301097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS24	NM_033022.4	c.391-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372360.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS24	ENST00000372360.9	c.391-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_033022.4	P4

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9573 AN: 152126 Hom.: 1012 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0174 AC: 4365 AN: 251212 Hom.: 383 AF XY: 0.0131 AC XY: 1783 AN XY: 135764

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0110

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000854

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00741 AC: 10826 AN: 1460948 Hom.: 919 Cov.: 30 AF XY: 0.00652 AC XY: 4741 AN XY: 726896

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0227

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000666

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0630 AC: 9590 AN: 152244 Hom.: 1012 Cov.: 33 AF XY: 0.0606 AC XY: 4509 AN XY: 74452

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0119 Hom.: 343

Bravo AF: 0.0726

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.214 AC: 945

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0216 AC: 2622

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2016	- -

Diamond-Blackfan anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

RPS24-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Diamond-Blackfan anemia 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.66
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	P;P;P;P
PROVEAN	Benign	1.4	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.18
ClinPred		0.0069	T
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs7899453; hg19: chr10-79799959;