5-14374244-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_007118.4(TRIO):c.3232C>T(p.Arg1078Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R1078Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:1

Conservation

PhyloP100: 0.300

Publications

1 publications found

Variant links:

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]

TRIO Gene-Disease associations (from GenCC):

syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
intellectual developmental disorder, autosomal dominant 63, with macrocephaly
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

TRIO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_007118.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-14374245-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 830227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 5-14374244-C-T is Pathogenic according to our data. Variant chr5-14374244-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4 link	c.3232C>T	p.Arg1078Trp	missense_variant	Exon 19 of 57	ENST00000344204.9	NP_009049.2	O75962-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9 link	c.3232C>T	p.Arg1078Trp	missense_variant	Exon 19 of 57	1	NM_007118.4	ENSP00000339299.4		O75962-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1078 of the TRIO protein (p.Arg1078Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a neurodevelopmental disorder (PMID: 32109419). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRIO protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRIO function (PMID: 32109419). For these reasons, this variant has been classified as Pathogenic. -

Feb 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect by altering overall protein folding and/or signaling (PMID: 32109419); Not observed at significant frequency 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: 33619735, 32109419, 33568469, 31130284, 35174982, 36717740, 35322241, 36987741, 33057194, 35982159) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

Pathogenic:4

Dec 17, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM6 moderated, PP2 supporting -

Sep 23, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Jun 21, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

Pathogenic:3

Mar 13, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32109419, 32109419). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000449111 /PMID: 32109419 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 32109419, 32109419). Different missense changes at the same codon (p.Arg1078Gln, p.Arg1078Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000830226, VCV000830227 /PMID: 32109419). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 10, 2020

SIB Swiss Institute of Bioinformatics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 63, with macrocephaly. 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 upgraded to very strong); 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). -

Mar 31, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Autosomal recessive nonsyndromic hearing loss 28

Pathogenic:1

Nov 03, 2017

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Oct 14, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome;C5394205:Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP2+PS4_Moderate+PS2+PP4+PM5_Supporting -

Intellectual disability

Uncertain:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T;T

Eigen

Benign

-0.043

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.39

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.4

M;.;.

PhyloP100

0.30

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.2

D;D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.86

MutPred

0.50

Gain of catalytic residue at L1076 (P = 0.0059);.;.;

MVP

0.68

MPC

2.0

ClinPred

0.93

GERP RS

0.49

Varity_R

0.84

gMVP

0.81

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over