Variant 5-14487962-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_007118.4(TRIO):c.7334C>A(p.Pro2445Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,954 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2445L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.32297623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4 linkuse as main transcript	c.7334C>A	p.Pro2445Gln	missense_variant	48/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9 linkuse as main transcript	c.7334C>A	p.Pro2445Gln	missense_variant	48/57	1	NM_007118.4	P1	O75962-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1398954

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.26e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2020

Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

0.036

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.92

N;.

REVEL

Benign

0.094

Sift

Uncertain

0.011

D;.

Sift4G

Uncertain

0.021

D;D

Polyphen

1.0

D;.

Vest4

0.28

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0071);.;

MVP

0.57

MPC

0.29

ClinPred

0.39

GERP RS

4.9

Varity_R

0.15

gMVP

0.26

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over