rs1555841301

chr19-41869043-G-Achr19-41869043-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001022.4(RPS19):c.185G>A(p.Arg62Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS19 NM_001022.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.96

Genes affected

RPS19 (HGNC:10402): (ribosomal protein S19) 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 S19E family of ribosomal proteins. It is located in the cytoplasm. Mutations in this gene cause Diamond-Blackfan anemia (DBA), a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors, in a subset of patients. This suggests a possible extra-ribosomal function for this gene in erythropoietic differentiation and proliferation, in addition to its ribosomal function. Higher expression levels of this gene in some primary colon carcinomas compared to matched normal colon tissues has been observed. 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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_001022.4 (RPS19) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001022.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41869042-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 19-41869043-G-A is Pathogenic according to our data. Variant chr19-41869043-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 463372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41869043-G-A is described in Lovd as [Pathogenic]. Variant chr19-41869043-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS19	NM_001022.4	c.185G>A	p.Arg62Gln	missense_variant	4/6	ENST00000598742.6
RPS19	NM_001321483.2	c.185G>A	p.Arg62Gln	missense_variant	4/6
RPS19	NM_001321484.2	c.185G>A	p.Arg62Gln	missense_variant	4/6
RPS19	NM_001321485.2	c.198G>A	p.Ala66=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS19	ENST00000598742.6	c.185G>A	p.Arg62Gln	missense_variant	4/6	1	NM_001022.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Diamond-Blackfan anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2023	The p.R62Q pathogenic mutation (also known as c.185G>A), located in coding exon 3 of the RPS19 gene, results from a G to A substitution at nucleotide position 185. The arginine at codon 62 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first described in a 2-month-old infant with Diamond-Blackfan anemia (DBA) (Cmejla R, et al. Blood Cells Mol. Dis. 2000 Apr; 26(2):124-32). Subsequent studies have identified this mutation in additional infants and probands with DBA, and segregation with disease in families has been reported (Proust A et al. Hematol J. 2003; 4(2):132-6; Konno Y et al. Haematologica. 2010 Aug; 95(8):1293-9; Ichimura T et al. Int J Hematol. 2017 Apr;105(4):515-520; Muramatsu H. Genet. Med. 2017 07;19(7):796-802; Cole S et al. Front Genet, 2022 Jul;13:914141). This mutation has been reported to disrupt protein stability and prevent protein assembly into a mature ribosome in functional assays (Angelini M, et al. Hum. Mol. Genet. 2007 Jul; 16(14):1720-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 62 of the RPS19 protein (p.Arg62Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Diamond-Blackfan anaemia (DBA) (PMID: 10753603, 12750732, 15384984, 18412286, 20378560). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463372). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects RPS19 function (PMID: 16159874, 17053056, 17082006, 17517689, 17726054, 24952648). This variant disrupts the p.Arg62 amino acid residue in RPS19. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15384984, 17517689, 18412286, 20606162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

RPS19-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2023

The RPS19 c.185G>A variant is predicted to result in the amino acid substitution p.Arg62Gln. This variant has been reported in the heterozygous state in multiple unrelated individuals and families with Diamond-Blackfan anemia (DBA) (see for example, Cmejla R et al. 2000. PubMed ID: 10753603; Gazda HT et al. 2004. PubMed ID: 15384984; Konno Y et al. 2010. PubMed ID: 20378560; Ichimura T et al. 2016. PubMed ID: 27882484). In one large family, this variant segregated with DBA in 9 of 10 carriers (Cole S et al. 2022. PubMed ID: 35923690). In vitro functional studies show this variant significantly inhibits the rate of protein synthesis compared to control, is degraded more rapidly compared to control, and results in altered pre-rRNA processing leading to impaired ribosome biogenesis (Cmejlova J et al 2006. PubMed ID: 17082006; Angelini M et al 2007. PubMed ID: 17517689; Choesmel V et al. 2007 PubMed ID: 17053056). Another missense change impacting the same amino acid (p.Arg62Trp) has been reported in individuals with DBA and has also been shown to negatively impact RPS19 protein function, suggesting that the Arg62 residue is critical to protein function (Gazda HT et al 2004. PubMed ID: 15384984; Devlin et al. 2010. PubMed ID: 20606162). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, the c.185G>A (p.Arg62Gln) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.9	H;.;H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		0.82	P;.;P;P
Vest4		0.86
MutPred		0.98		Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92

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: rs1555841301; hg19: chr19-42373113;