rs104894711

Variant names:

• chr19-41869042-C-T
• rs104894711
• NM_001022.4:c.184C>T
• RPS19 p.Arg62Trp

Your query was ambiguous. Multiple possible variants found:

• chr19-41869042-C-T
• chr19-41869042-C-A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004047404: This variant has been reported to affect RPS19 protein function (Devlin EE et al)." and additional evidence is available in ClinVar. 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.20
• Publications: 20 publications found

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]

RPS19 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Diamond-Blackfan anemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004047404: This variant has been reported to affect RPS19 protein function (Devlin EE et al).; SCV000589354: 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); SCV001230721: Experimental studies have shown that this missense change affects RPS19 function (PMID: 20395159, 20606162).; SCV002717112: 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).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 VariationId 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/Likely_pathogenic. ClinVar VariationId is 6314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	NM_001022.4	MANE Select	c.184C>T	p.Arg62Trp	missense	Exon 4 of 6	NP_001013.1	B0ZBD0
	RPS19	NM_001321485.2		c.197C>T	p.Ala66Val	missense	Exon 4 of 6	NP_001308414.1
	RPS19	NM_001321483.2		c.184C>T	p.Arg62Trp	missense	Exon 4 of 6	NP_001308412.1	B0ZBD0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS19	ENST00000598742.6	TSL:1 MANE Select	c.184C>T	p.Arg62Trp	missense	Exon 4 of 6	ENSP00000470972.1	P39019
	RPS19	ENST00000593863.5	TSL:3	c.184C>T	p.Arg62Trp	missense	Exon 4 of 6	ENSP00000470004.1	P39019
	RPS19	ENST00000600467.6	TSL:2	c.184C>T	p.Arg62Trp	missense	Exon 4 of 6	ENSP00000469228.2	P39019

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Diamond-Blackfan anemia 1 (3)
2	-	-	Diamond-Blackfan anemia (2)
1	-	-	not provided (1)
1	-	-	RPS19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.2
Sift4G	Benign	0.36	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894711;

hg19: chr19-42373112;