Genetic Variant TRIO:p.Pro2445Gln (chr5-14487962-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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. 14/22 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

Publications

0 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: Illumina, ClinGen
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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

TRIO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32297623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007118.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	NM_007118.4	MANE Select	c.7334C>A	p.Pro2445Gln	missense	Exon 48 of 57	NP_009049.2
	TRIO	NR_134469.2		n.7486+232C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRIO	ENST00000344204.9	TSL:1 MANE Select	c.7334C>A	p.Pro2445Gln	missense	Exon 48 of 57	ENSP00000339299.4	O75962-1
TRIO	ENST00000515144.5	TSL:1	n.6252C>A		non_coding_transcript_exon	Exon 43 of 43
TRIO	ENST00000513206.5	TSL:5	c.6533C>A	p.Pro2178Gln	missense	Exon 44 of 51	ENSP00000426342.2	E7EPJ7

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

African (AFR)

AF:

0.00

AC:

AN:

31650

American (AMR)

AF:

0.00

AC:

AN:

36374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25032

East Asian (EAS)

AF:

0.00

AC:

AN:

35956

South Asian (SAS)

AF:

0.00

AC:

AN:

79416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4974

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080258

Other (OTH)

AF:

0.00

AC:

AN:

57872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

Eigen

Benign

0.036

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.47

MutationAssessor

Benign

2.0

PhyloP100

3.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.92

REVEL

Benign

0.094

Sift

Uncertain

0.011

Sift4G

Uncertain

0.021

Polyphen

1.0

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

PromoterAI

-0.0019

Neutral

(source)

Varity_R

0.15

gMVP

0.26

Mutation Taster

=89/11

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over