19-41869042-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001022.4(RPS19):c.184C>T(p.Arg62Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R62Q) 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:6
• Conservation: PhyloP100: 3.20

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 16 ACMG points.

• 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 chr19-41869043-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 19-41869042-C-T is Pathogenic according to our data. 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. Variant chr19-41869042-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS19	NM_001022.4	c.184C>T	p.Arg62Trp	missense_variant	4/6	ENST00000598742.6
RPS19	NM_001321485.2	c.197C>T	p.Ala66Val	missense_variant	4/6
RPS19	NM_001321483.2	c.184C>T	p.Arg62Trp	missense_variant	4/6
RPS19	NM_001321484.2	c.184C>T	p.Arg62Trp	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS19	ENST00000598742.6	c.184C>T	p.Arg62Trp	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The RPS19 c.184C>T (p.Arg62Trp) variant has been reported in heterozygous state in individuals affected with Diamond-Blackfan anemia (Muramatsu H et al). In at least one individual the variant was observed to be de novo. The p.Arg62Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 62 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to affect RPS19 protein function (Devlin EE et al). This variant disrupts the p.Arg62 amino acid residue in RPS19. The amino acid change p.Arg62Trp in RPS19 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Diamond-Blackfan anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2014	The p.R62W pathogenic mutation (also known as c.184C>T), located in coding exon 3 of the RPS19 gene, results from a C to T substitution at nucleotide position 184. The arginine at codon 62 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation was first described in two unrelated individuals with Diamond Blackfan anemia; the mutation segregated with two affected individuals in one family and was reportedly de novo in the second individual (Draptchinskaia N et al. Nat Genet. 1999; 21(2):169-75). One functional study suggested this mutation allowed accelerated degradation of the protein and prevented assembly into the ribosomal complex (Angelini M et al. Hum Mol Genet. 2007; 16(14):1720-7). Another functional study found cells with this mutation had significantly reduced binding capacity for its own mRNA compared to wild-type RPS19 which could impact its regulation (Schuster J et al. Blood Cells Mol Dis. 2010; 45(1):23-8). Based on the supporting evidence, p.R62W is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 09, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 10753603, 12750732, 15384984, 16159874, 17053056, 17082006, 17517689, 17726054, 18412286, 20378560, 24952648). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RPS19 function (PMID: 20395159, 20606162). 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. ClinVar contains an entry for this variant (Variation ID: 6314). This missense change has been observed in individual(s) with clinical features of Diamond-Blackfan anemia (PMID: 9988267, 12586610, 28102861). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 62 of the RPS19 protein (p.Arg62Trp). -

RPS19-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

The RPS19 c.184C>T variant is predicted to result in the amino acid substitution p.Arg62Trp. This variant has been reported in individuals with Diamond-Blackfan anaemia or bone marrow failure related disease (Draptchinskaia et al. 1999. PubMed ID: 9988267; Muramatsu et al. 2017. PubMed ID: 28102861. Table S1; Blombery et al. 2021. PubMed ID: 32054657; Gálvez et al. 2021. PubMed ID: 33718801. Table S5; Grossi et al. 2021. PubMed ID: 34573280). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2021

Published functional studies demonstrate severe phenotypic defects in mice and a reduced binding capacity of the RPS19 protein (Devlin et al., 2010; Schuster et al., 2010); Not observed at significant frequency in large population cohorts (Lek et al., 2016); A different missense change at this residue (p.(R62Q)) has been reported pathogenic in the published literature and at GeneDx in association with Diamond-Blackfan anemia (Cmejla et al., 2000; Muramatsu et al., 2017; Ichimura et al., 2017); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12351378, 17726054, 18768533, 22160079, 17517689, 20395159, 20606162, 15384984, 16537118, 15075082, 16159874, 16266891, 21435507, 25069755, 18217898, 19765279, 21435504, 12586610, 20378560, 27329125, 30077612, 33810313, 34573280, 9988267, 28102861, 32054657, 33718801, 10753603, 27882484) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D
MutationTaster	Benign	1.0	D
Sift4G	Benign	0.36	T
MVP		0.97
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs104894711; hg19: chr19-42373112;