Variant chr5-14143738-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_007118.4(TRIO):c.13A>G(p.Ser5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000592 in 979,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0170

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 Likely_benign. Variant got -5 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=0.077849686).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIO	NM_007118.4 linkuse as main transcript	c.13A>G	p.Ser5Gly	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.13A>G	p.Ser5Gly	missense_variant	1/57	1	NM_007118.4	ENSP00000339299	P1	O75962-1
TRIO	ENST00000698541.1 linkuse as main transcript	c.13A>G	p.Ser5Gly	missense_variant	1/37			ENSP00000513786
TRIO	ENST00000502816.1 linkuse as main transcript	n.37A>G		non_coding_transcript_exon_variant	1/5	2
TRIO	ENST00000505971.5 linkuse as main transcript	n.37A>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000897

AC:

AN:

144880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00178

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00329

Gnomad NFE

AF:

0.0000612

Gnomad OTH

AF:

0.000500

GnomAD4 exome

AF:

0.0000539

AC:

AN:

834598

Hom.:

Cov.:

AF XY:

0.0000519

AC XY:

AN XY:

385700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00346

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000197

Gnomad4 OTH exome

AF:

0.000437

GnomAD4 genome

AF:

0.0000897

AC:

AN:

144880

Hom.:

Cov.:

AF XY:

0.0000852

AC XY:

AN XY:

70400

show subpopulations

Gnomad4 AFR

AF:

0.0000248

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00178

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000612

Gnomad4 OTH

AF:

0.000500

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.13A>G (p.S5G) alteration is located in exon 1 (coding exon 1) of the TRIO gene. This alteration results from a A to G substitution at nucleotide position 13, causing the serine (S) at amino acid position 5 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.049

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.25

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.11

REVEL

Benign

0.059

Sift

Pathogenic

0.0

Polyphen

0.14

Vest4

0.17

MutPred

0.19

Loss of glycosylation at S5 (P = 0.0011);

MVP

0.37

MPC

0.77

ClinPred

0.18

GERP RS

-0.10

Varity_R

0.19

gMVP

0.12

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