19-41860777-G-A

Position:

• chr19-41860777-G-A

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.3G>A​(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. 1/1 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: RPS19 NM_001022.4 start_lost, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.90

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: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41860777-G-A is Pathogenic according to our data. Variant chr19-41860777-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 860401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41860777-G-A is described in Lovd as [Pathogenic]. Variant chr19-41860777-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS19	NM_001022.4	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/6	ENST00000598742.6
RPS19	NM_001321485.2	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/6
RPS19	NM_001321483.2	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/6
RPS19	NM_001321484.2	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS19	ENST00000598742.6	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/6	1	NM_001022.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2017	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the RPS19 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This mutation was detected in multiple individuals with Diamond-Blackfan anemia (Proust A et al. Hematol. J., 2003;4:132-6; Chae H et al. Exp. Mol. Med., 2014 Mar;46:e88; Delaporta P et al. Pediatr Blood Cancer, 2014 Dec;61:2249-55). In addition, two mutations at the same codon, c.3G>C and c.3G>T, were reported in affected individuals (Ramenghi U et al. Blood Cells Mol. Dis., 2000 Oct;26:417-22; Orfali KA et al. Br. J. Haematol., 2004 Apr;125:243-52). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 29, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 860401). This sequence change affects the initiator methionine of the RPS19 mRNA. The next in-frame methionine is located at codon 75. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Diamond-Blackfan anemia (PMID: 12750732, 20378560, 20603584, 27329125, 28102861, 28376382). This variant is also known as ATG3ATA, g.3G>A. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.98
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0182);Gain of catalytic residue at M1 (P = 0.0182);Gain of catalytic residue at M1 (P = 0.0182);Gain of catalytic residue at M1 (P = 0.0182);Gain of catalytic residue at M1 (P = 0.0182);
MVP		0.94
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.61

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: rs138938035; hg19: chr19-42364847; COSMIC: COSV55744167; COSMIC: COSV55744167;