rs587780563
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_003491.4(NAA10):c.346C>T(p.Arg116Trp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003491.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAA10 | NM_003491.4 | c.346C>T | p.Arg116Trp | missense_variant | 6/8 | ENST00000464845.6 | |
NAA10 | NM_001256120.2 | c.328C>T | p.Arg110Trp | missense_variant | 6/8 | ||
NAA10 | NM_001256119.2 | c.341+205C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAA10 | ENST00000464845.6 | c.346C>T | p.Arg116Trp | missense_variant | 6/8 | 1 | NM_003491.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Ogden syndrome Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000139644). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). A different missense change at the same codon (p.Arg116Gln) has been reported to be associated with NAA10 related disorder (ClinVar ID: VCV001326724). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 29, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 08, 2019 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Medical Genetics, University of Torino | Oct 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Mar 31, 2016 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2021 | Published functional studies demonstrate a damaging effect; a reduction in the catalytic activity (Popp et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25099252, 23871722, 23020937, 27296530, 27094817, 29957440, 30577886) - |
NAA10-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2023 | The NAA10 c.346C>T variant is predicted to result in the amino acid substitution p.Arg116Trp. This variant has been reported in the heterozygous and hemizygous states in patients with intellectual disability, development delay and eyelid myoclonus; in the majority of cases, this variant was found to be de novo (see for example, Rauch et al. 2012. PubMed ID: 23020937; Valentine et al. 2018. PubMed ID: 29957440; Baker et al. 2019. PubMed ID: 30577886). This variant was also confirmed to be de novo in an individual with intellectual disability and microcephaly tested at PreventionGenetics. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare in the general population. This variant is interpreted as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo change in several individuals with NAA10-related disorder (PMID: 25099252, 29957440). In vitro studies using N-terminal acetylation assays demonstrated protein with this variant had significant reduction in the catalytic activity of the enzyme in comparison to wild type protein (PMID: 25099252). The c.346C>T (p.Arg116Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.346C>T (p.Arg116Trp) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.346C>T (p.Arg116Trp) variant is classified as a Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at