19-41860794-AAG-CTCCAGCATCCAGTT

Position:

• chr19-41860794-AAG-CTCCAGCATCCAGTT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_001022.4(RPS19):​c.20_22delinsCTCCAGCATCCAGTT​(p.Lys7_Asp8delinsThrProAlaSerSerTyr) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS19 NM_001022.4 protein_altering
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain 40S ribosomal protein S19 (size 143) in uniprot entity RS19_HUMAN there are 70 pathogenic changes around while only 3 benign (96%) in NM_001022.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001022.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS19	NM_001022.4	c.20_22delinsCTCCAGCATCCAGTT	p.Lys7_Asp8delinsThrProAlaSerSerTyr	protein_altering_variant	2/6	ENST00000598742.6	NP_001013.1
RPS19	NM_001321483.2	c.20_22delinsCTCCAGCATCCAGTT	p.Lys7_Asp8delinsThrProAlaSerSerTyr	protein_altering_variant	2/6		NP_001308412.1
RPS19	NM_001321484.2	c.20_22delinsCTCCAGCATCCAGTT	p.Lys7_Asp8delinsThrProAlaSerSerTyr	protein_altering_variant	2/6		NP_001308413.1
RPS19	NM_001321485.2	c.20_22delinsCTCCAGCATCCAGTT	p.Lys7_Asp8delinsThrProAlaSerSerTyr	protein_altering_variant	2/6		NP_001308414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS19	ENST00000598742.6	c.20_22delinsCTCCAGCATCCAGTT	p.Lys7_Asp8delinsThrProAlaSerSerTyr	protein_altering_variant	2/6	1	NM_001022.4	ENSP00000470972	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 16, 2023

Variant summary: RPS19 c.20_22delins15 (p.Lys7_Asp8delinsThrProAlaSerSerTyr) results in an in-frame deletion-insertion that is predicted to delete 2 amino acid and insert 6 amino acids from the protein. The variant was absent in 251432 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.20_22delins15 in individuals affected with Diamond-Blackfan Anemia 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42364864;