chr5-14394102-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_007118.4(TRIO):c.4283G>A(p.Arg1428Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TRIO
NM_007118.4 missense
NM_007118.4 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
TRIO (HGNC:12303): (trio Rho guanine nucleotide exchange factor) This gene encodes a large protein that functions as a GDP to GTP exchange factor. This protein promotes the reorganization of the actin cytoskeleton, thereby playing a role in cell migration and growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_007118.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, TRIO
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 5-14394102-G-A is Pathogenic according to our data. Variant chr5-14394102-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-14394102-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-14394102-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRIO | NM_007118.4 | c.4283G>A | p.Arg1428Gln | missense_variant | 28/57 | ENST00000344204.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRIO | ENST00000344204.9 | c.4283G>A | p.Arg1428Gln | missense_variant | 28/57 | 1 | NM_007118.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome Pathogenic:7Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 30, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in one patient with global developmental delay [PMID 27418539] - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 31, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 06, 2021 | This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PS3_SUP, PM1_SUP, PM2_SUP, PP2, PP3 - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Sep 10, 2020 | This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 44, with microcephaly. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Sep 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:32109419). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000253084). The variant has been previously reported as de novo in a similarly affected individual (PMID: 32109419). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
TRIO-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 27, 2023 | The TRIO c.4283G>A variant is predicted to result in the amino acid substitution p.Arg1428Gln. This variant has been reported to occur de novo in individuals with TRIO-related autosomal dominant intellectual developmental disorder (Patient 4; Pengelly et al. 2016. PubMed ID: 27418539; Barbosa et al. 2020. PubMed ID: 32109419). Functional studies suggest this variant impairs Trio-mediated Rac1 activation (Pengelly et al. 2016. PubMed ID: 27418539). This variant occurs in the Dbl homology domain (DH1), which is considered a mutation hotspot in the TRIO protein (Sadybekov. 2017. PubMed ID: 28928363). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2023 | Published functional studies demonstrate a damaging effect (reduced ability to activate Rac1 as compared to wild-type) (Pengelly et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28928363, 24782526, 27418539, 32109419, 31785789, 33038108, 35599849, 34697084, 36717740) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0256);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at