chr19-41860842-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BP6BS2
The NM_001022.4(RPS19):c.68A>G(p.Lys23Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,613,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RPS19 | NM_001022.4 | c.68A>G | p.Lys23Arg | missense_variant | Exon 2 of 6 | ENST00000598742.6 | NP_001013.1 | |
RPS19 | NM_001321485.2 | c.68A>G | p.Lys23Arg | missense_variant | Exon 2 of 6 | NP_001308414.1 | ||
RPS19 | NM_001321483.2 | c.68A>G | p.Lys23Arg | missense_variant | Exon 2 of 6 | NP_001308412.1 | ||
RPS19 | NM_001321484.2 | c.68A>G | p.Lys23Arg | missense_variant | Exon 2 of 6 | NP_001308413.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251464Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135916
GnomAD4 exome AF: 0.000404 AC: 590AN: 1461084Hom.: 0 Cov.: 30 AF XY: 0.000402 AC XY: 292AN XY: 726852
GnomAD4 genome AF: 0.000276 AC: 42AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74490
ClinVar
Submissions by phenotype
Diamond-Blackfan anemia Uncertain:1Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 23 of the RPS19 protein (p.Lys23Arg). This variant is present in population databases (rs143477104, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RPS19-related conditions. ClinVar contains an entry for this variant (Variation ID: 329392). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
DNA sequence analysis of the RPS19 gene demonstrated a sequence change, c.68A>G, in exon 2 that results in an amino acid change, p.Lys23Arg. This sequence change does not appear to have been previously described in patients with RPS19-related disorders and has been described in the gnomAD database with a frequency of 0.04% in European populations (dbSNP rs143477104). The p.Lys23Arg change affects a moderately conserved amino acid residue located in a domain of the RPS19 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys23Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys23Arg change remains unknown at this time. -
not provided Uncertain:1
The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified as a common polymorphism in the RPS19 gene, and authors presumed this variant to be benign (Aspesi et al., 2018); This variant is associated with the following publications: (PMID: 29766597) -
Diamond-Blackfan anemia 1 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at