19-41860786-T-TA

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.13dup(p.Thr5AsnfsTer46) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS19 NM_001022.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.40

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 131 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41860786-T-TA is Pathogenic according to our data. Variant chr19-41860786-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 858368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS19	NM_001022.4	c.13dup	p.Thr5AsnfsTer46	frameshift_variant	2/6	ENST00000598742.6
RPS19	NM_001321483.2	c.13dup	p.Thr5AsnfsTer46	frameshift_variant	2/6
RPS19	NM_001321484.2	c.13dup	p.Thr5AsnfsTer46	frameshift_variant	2/6
RPS19	NM_001321485.2	c.13dup	p.Thr5AsnfsTer46	frameshift_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS19	ENST00000598742.6	c.13dup	p.Thr5AsnfsTer46	frameshift_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	Jun 04, 2018	The c.13dupA pathogenic mutation, located in coding exon 1 of the RPS19 gene, results from a duplication of A at nucleotide position 13, causing a translational frameshift with a predicted alternate stop codon (p.T5Nfs*46). This mutation was identified in one individual with Diamond-Blackfan anemia (DBA) (Draptchinskaia N et al. Nat. Genet., 1999 Feb;21:169-75). Cultured cells from a transfusion dependent individual with DBA demonstrated reduced RPS19 mRNA levels (Chatr-Aryamontri A et al. Hum. Mutat., 2004 Dec;24:526-33). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2019	This sequence change creates a premature translational stop signal (p.Thr5Asnfs*46) in the RPS19 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) and a stillborn fetus affected with Diamond-Blackfan anaemia (PMID: 9988267, 23349008). Loss-of-function variants in RPS19 are known to be pathogenic (PMID: 20960466). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs149420497; hg19: chr19-42364856;