5-14143766-C-T

Position:

chr5-14143766-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_007118.4(TRIO):c.41C>T(p.Ser14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,002,186 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 1 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.721

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRIO. . Gene score misZ 5.3161 (greater than the threshold 3.09). Trascript score misZ 4.6722 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.028496742).

BP6

Variant 5-14143766-C-T is Benign according to our data. Variant chr5-14143766-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 501649.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00129 (189/146340) while in subpopulation NFE AF= 0.00243 (160/65818). AF 95% confidence interval is 0.00212. There are 2 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIO	NM_007118.4 linkuse as main transcript	c.41C>T	p.Ser14Phe	missense_variant	1/57	ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9 linkuse as main transcript	c.41C>T	p.Ser14Phe	missense_variant	1/57	1	NM_007118.4	ENSP00000339299	P1	O75962-1
TRIO	ENST00000698541.1 linkuse as main transcript	c.41C>T	p.Ser14Phe	missense_variant	1/37			ENSP00000513786
TRIO	ENST00000502816.1 linkuse as main transcript	n.65C>T		non_coding_transcript_exon_variant	1/5	2
TRIO	ENST00000505971.5 linkuse as main transcript	n.65C>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes

AF:

0.00129

AC:

189

AN:

146272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000407

Gnomad ASJ

AF:

0.000591

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.000986

GnomAD3 exomes

AF:

0.00314

AC:

AN:

318

Hom.:

AF XY:

0.00556

AC XY:

AN XY:

180

show subpopulations

Gnomad NFE exome

AF:

0.00321

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00237

AC:

2029

AN:

855846

Hom.:

Cov.:

AF XY:

0.00237

AC XY:

940

AN XY:

397382

show subpopulations

Gnomad4 AFR exome

AF:

0.000369

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000349

Gnomad4 NFE exome

AF:

0.00254

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00129

AC:

189

AN:

146340

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

71216

show subpopulations

Gnomad4 AFR

AF:

0.000440

Gnomad4 AMR

AF:

0.000406

Gnomad4 ASJ

AF:

0.000591

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000119

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.000978

Alfa

AF:

0.00265

Hom.:

Bravo

AF:

0.00114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TRIO: BS1 -

TRIO-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.050

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.99

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.24

REVEL

Benign

0.095

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.68

Vest4

0.13

MVP

0.068

MPC

0.91

ClinPred

0.21

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.17

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over