rs730882213
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_138422.4(ADAT3):c.430G>A(p.Val144Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,500,450 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000044 ( 0 hom. )
Consequence
ADAT3
NM_138422.4 missense
NM_138422.4 missense
Scores
3
8
3
Clinical Significance
Conservation
PhyloP100: 2.06
Genes affected
ADAT3 (HGNC:25151): (adenosine deaminase tRNA specific 3) This gene encodes a subunit of a tRNA-specific adenosine deaminase. This heterodimeric enzyme converts adenosine to inosine in the tRNA anticodon. A mutation in this gene causes a syndrome characterized by intellectual disability and strabismus. This gene shares its 5' exon with the overlapping gene, secretory carrier membrane protein 4 (Gene ID: 113178). [provided by RefSeq, Jul 2016]
SCAMP4 (HGNC:30385): (secretory carrier membrane protein 4) Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane proteins implicated in membrane trafficking. Most SCAMPs (e.g., SCAMP1; MIM 606911) have N-terminal cytoplasmic NPF (arg-pro-phe) repeats, 4 central transmembrane regions, and a short C-terminal cytoplasmic tail. These SCAMPs likely have a role in endocytosis that is mediated by their NPF repeats. Other SCAMPs, such as SCAMP4, lack the NPF repeats and are therefore unlikely to function in endocytosis (summary by Fernandez-Chacon and Sudhof, 2000 [PubMed 11050114]).[supplied by OMIM, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.84
PP5
?
Variant 19-1912477-G-A is Pathogenic according to our data. Variant chr19-1912477-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1912477-G-A is described in Lovd as [Pathogenic]. Variant chr19-1912477-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAT3 | NM_138422.4 | c.430G>A | p.Val144Met | missense_variant | 2/2 | ENST00000329478.4 | |
SCAMP4 | NM_079834.4 | c.-41-2502G>A | intron_variant | ENST00000316097.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAT3 | ENST00000329478.4 | c.430G>A | p.Val144Met | missense_variant | 2/2 | 1 | NM_138422.4 | P1 | |
SCAMP4 | ENST00000316097.13 | c.-41-2502G>A | intron_variant | 1 | NM_079834.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000445 AC: 6AN: 1348432Hom.: 0 Cov.: 30 AF XY: 0.00000601 AC XY: 4AN XY: 665022
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability-strabismus syndrome Pathogenic:14
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 06, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breakthrough Genomics, Breakthrough Genomics | - | This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant (also known as V128M in literature) was previously reported in patients with intellectual disability and considered as founder mutation in the Saudi Arabian population [PMID: 26842963, 23620220, 32214227]. Functional studies using cell lines derived from intellectual disability-affected individuals showed a severe reduction in tRNA deaminase activity [PMID: 31263000]. - |
Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Pathogenic, no assertion criteria provided | research | Section for Clinical Neurogenetics, University of Tübingen | Aug 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 03, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Aug 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Department of Biochemistry, Faculty of Medicine, University of Khartoum | Mar 25, 2021 | We detected the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) in two female siblings with Mental retardation, autosomal recessive 36 using whole-exome sequencing. We validated the variant's status in the patients using Sanger sequencing and detected it in a heterozygous status in their parents. Multiple reports previously classified the variant NM_138422.3(ADAT3): c.430G>A (p.Val144Met, rs730882213) as pathogenic (Alazami et al., 2013; El-Hattab et al., 2016). - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Hadassah Hebrew University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The homozgous p.Val144Met variant was identified by our study in one individual with mental retardation. Of note, a first cousin who was noted to also have mental retardation was a carrier for this variant. The p.Val144Met variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely 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 25, 2023 | Also known as p.V128M; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32860008, 31130284, 26633546, 25558065, 30296593, 30529455, 31263000, 32552793, 32214227, 33101984, 28454995, 30202406, 35118659, 26842963, 23620220) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
REVEL
Uncertain
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at