Genetic Variant TRIO:p.Ser26Leu (chr5-14143802-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007118.4(TRIO):c.77C>T(p.Ser26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,048,858 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.489

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: 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11027214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4 link	c.77C>T	p.Ser26Leu	missense_variant	Exon 1 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.77C>T	p.Ser26Leu	missense_variant	Exon 1 of 57	1	NM_007118.4	ENSP00000339299.4		O75962-1

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

147150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000454

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000222

AC:

AN:

901708

Hom.:

Cov.:

AF XY:

0.00000237

AC XY:

AN XY:

421266

show subpopulations

African (AFR)

AF:

0.0000575

AC:

AN:

17404

American (AMR)

AF:

0.00

AC:

AN:

2996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7226

East Asian (EAS)

AF:

0.00

AC:

AN:

8308

South Asian (SAS)

AF:

0.00

AC:

AN:

17888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1976

European-Non Finnish (NFE)

AF:

0.00000124

AC:

AN:

807014

Other (OTH)

AF:

0.00

AC:

AN:

31452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

AF:

0.0000272

AC:

AN:

147150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71646

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40886

American (AMR)

AF:

0.00

AC:

AN:

14816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000454

AC:

AN:

66140

Other (OTH)

AF:

0.00

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.49

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.34

REVEL

Benign

0.087

Sift

Benign

0.072

Sift4G

Benign

0.34

Polyphen

0.0080

Vest4

0.15

MutPred

0.20

Loss of glycosylation at S26 (P = 1e-04);

MVP

0.16

MPC

0.75

ClinPred

0.075

GERP RS

1.4

PromoterAI

0.024

Neutral

(source)

Varity_R

0.057

gMVP

0.14

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over