16-89562954-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000977.4(RPL13):c.548G>A(p.Arg183His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183L) has been classified as Pathogenic.
Frequency
Consequence
NM_000977.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPL13 | NM_000977.4 | c.548G>A | p.Arg183His | missense_variant | 6/6 | ENST00000311528.10 | |
RPL13 | NM_033251.2 | c.548G>A | p.Arg183His | missense_variant | 5/5 | ||
RPL13 | NM_001243131.1 | c.407G>A | p.Arg136His | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPL13 | ENST00000311528.10 | c.548G>A | p.Arg183His | missense_variant | 6/6 | 1 | NM_000977.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 2AN: 1447598Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 719432
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Spondyloepimetaphyseal dysplasia, Isidor-Toutain type Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | May 16, 2021 | A novel missense variant, c.548G>A in exon 6 of RPL13, was observed in heterozygous state in proband and in other affected family members. The variant is absent in gnomAD population database and in our in-house database of 1144 exomes. In-silico analysis tools (Mutation Taster, SIFT and REVEL) are consistent in predicting that the variant is damaging to RPL13 protein function. Clinical findings are in concordance with Spondyloepimetaphyseal dsyplasia, Isidor-Toutain type, thus the variant is interpreted to be likely pathogenic for the affected individuals. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 11, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Rare Disease Group, Clinical Genetics, Karolinska Institutet | Jul 25, 2022 | The Arg183His variant in RPL13 was absent from large population studies (gnomAD). Another variant affecting the same amino acid residue (p.Arg183Pro) has previously been reported in one individual with SEMDIST (OMIM #618728, Le Caignec et al. 2015). The variant has a accession number in ClinVar (SCV001984874) and classified as likely pathogenic. This variant was seen in an affected individual and her affected mother. In summary, the Arg183His meets our criterua to be classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000689803,VCV000804147, PMID:31630789). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
RPL13-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2023 | The RPL13 c.548G>A variant is predicted to result in the amino acid substitution p.Arg183His. This variant has been reported in a mother and child with spondyloepimetaphyseal dysplasia and was reported to be de novo in the mother (Díaz-González et al. 2023. PubMed ID: 37121912). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations in ClinVar of uncertain and likely pathogenic (https://ncbi.nlm.nih.gov/clinvar/variation/1030926/). Of note, a different missense variant affecting this amino acid (p.Arg183Pro) has been reported in an individual with spondyloepimetaphyseal dysplasia (Le Caignec et al. 2019. PubMed ID: 31630789). This variant is interpreted as likely pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the RPL13 protein (p.Arg183His). This variant has not been reported in the literature in individuals affected with RPL13-related conditions. 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. This variant disrupts the p.Arg183 amino acid residue in RPL13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31630789). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 1030926). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at