19-41869138-C-T

Position:

• chr19-41869138-C-T

Variant summary

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

The NM_001022.4(RPS19):​c.280C>T​(p.Arg94*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS19 NM_001022.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.660

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41869138-C-T is Pathogenic according to our data. Variant chr19-41869138-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41869138-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS19	NM_001022.4	c.280C>T	p.Arg94*	stop_gained	4/6	ENST00000598742.6	NP_001013.1
RPS19	NM_001321483.2	c.280C>T	p.Arg94*	stop_gained	4/6		NP_001308412.1
RPS19	NM_001321484.2	c.280C>T	p.Arg94*	stop_gained	4/6		NP_001308413.1
RPS19	NM_001321485.2	c.293C>T	p.Pro98Leu	missense_variant	4/6		NP_001308414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6	c.280C>T	p.Arg94*	stop_gained	4/6	1	NM_001022.4	ENSP00000470972.1

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS2_Moderate+PS4_Moderate+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2020

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect (dramatically reduced levels of expression and abnormal subcellular protein localization) (Cretien et al., 2008); This variant is associated with the following publications: (PMID: 9988267, 18768533, 10598818, 25525159) -

Diamond-Blackfan anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2014

The p.R94* pathogenic mutation (also known as c.280C>T), located in coding exon 3 of the RPS19 gene, results from a C to T substitution at nucleotide position 280. This changes the amino acid from an arginine to a stop codon within coding exon 3. This pathogenic mutation was first reported in two sisters with Diamond Blackfan anemia, as well as their unaffected mother; one sister had thumb malformations and a duplicated ureter and the other sister had congenital glaucoma, while the mother hand normal hemoglobin levels and no apparent malformations (Draptchinskaia N et al. Nat Genet. 1999; 21(2):169-75). An in vitro functional study found that cells with this pathogenic mutation resulted in a dramatic reduction of expression and a failure of nucleolar localization of the RPS19 protein (Crétien A et al. Haematologica. 2008; 93(11):1627-34). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.32	T
MetaRNN	Pathogenic	0.87	D
MVP		0.84
GERP RS		0.62
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: rs61762293; hg19: chr19-42373208; COSMIC: COSV99702725; COSMIC: COSV99702725;