10-78033902-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033022.4(RPS24):c.1A>G(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS24 NM_033022.4 start_lost, splice_region
• Scores: Splicing: ADA: 0.02431
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.71

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-78033902-A-G is Pathogenic according to our data. Variant chr10-78033902-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 265439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-78033902-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS24	NM_033022.4	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/6	ENST00000372360.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS24	ENST00000372360.9	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/6	1	NM_033022.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2018	For these reasons, this variant has been classified as Pathogenic. Experimental studies using patient derived fibroblasts have shown that this variant leads to decreased RPS24 and RPS19 protein levels, abnormal expression of cell cycle regulatory proteins, and reduced cellular proliferation (PMID: 19689926). This variant has been reported in an individual affected with Diamond-Blackfan anemia (PMID: 19689926). In addition, it has been observed to be de novo in an individual with clinical features of Diamond-Blackfan anemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 265439). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the RPS24 mRNA. The next in-frame methionine is located at codon 13. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2015	The p.M1? pathogenic mutation (also known as c.1A>G and p.M1V) is located in coding exon 1 of the RPS24 gene and results from a A to G substitution at nucleotide position 1. This is predicted to change the methionine to a valine at the initiation codon. This mutation was identified in a 26 year old female with Diamond-Blackfan anemia (DBA) who was transfusion dependent and had short stature and dysmorphic facial features. Functional studies of fibroblasts showed a reduction in protein and impaired cell growth in cells with this mutation (Badhai J et al. Biochim Biophys Acta. 2009; 1792(10):1036-42). It was also reported in another DBA patient (Ghemlas I et al, J. Med. Genet. 2015 Sep; 52(9):575-84). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2016

The c.1 A>G pathogenic variant in the RPS24 gene has been reported previously in association with Diamond-Blackfan anemia (Badhai et al., 2009; Ghemlas et al., 2015). The c.1 A>G 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. As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. We interpret c.1 A>G as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D;D;D
Polyphen		0.0040, 0.014, 0.21	.;B;B;.;B;.;.;.
Vest4		0.96, 0.96, 0.95, 0.65
MutPred		0.99		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.89
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.75
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.020		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: rs886039545; hg19: chr10-79793660;