rs1555841379

Positions:

• chr19-41869217-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001022.4(RPS19):​c.356+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS19 NM_001022.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.624

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-41869217-A-C is Pathogenic according to our data. Variant chr19-41869217-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436553.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-41869217-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS19	NM_001022.4	c.356+3A>C		splice_donor_region_variant, intron_variant		ENST00000598742.6
RPS19	NM_001321483.2	c.356+3A>C		splice_donor_region_variant, intron_variant
RPS19	NM_001321484.2	c.356+3A>C		splice_donor_region_variant, intron_variant
RPS19	NM_001321485.2	c.369+3A>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS19	ENST00000598742.6	c.356+3A>C		splice_donor_region_variant, intron_variant		1	NM_001022.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diamond-Blackfan anemia 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 21, 2021

DNA sequence analysis of the RPS19 gene in demonstrated a sequence change located near the canonical splice donor site in intron 4, c.356+3A>C. This sequence change does not appear to have been previously described in patients with RPS19-related disorders and has also not been described as a known benign sequence change in the RPS19 gene. Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the RPS19 gene, which would result in an abnormal protein, however functional studies have not been performed to prove this conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	34
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 6
DS_DL_spliceai		0.23		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555841379; hg19: chr19-42373287;