rs55900671

Positions:

chr5-14508238-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_007118.4(TRIO):c.9110A>T(p.Lys3037Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,058 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 58 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.98

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:

TRIO (HGNC:):

TRIO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.01017791).

BP6

Variant 5-14508238-A-T is Benign according to our data. Variant chr5-14508238-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 445657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00251 (383/152324) while in subpopulation EAS AF= 0.0504 (261/5176). AF 95% confidence interval is 0.0454. There are 10 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 383 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIO	NM_007118.4 linkuse as main transcript	c.9110A>T	p.Lys3037Met	missense_variant	57/57	ENST00000344204.9	NP_009049.2	O75962-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9 linkuse as main transcript	c.9110A>T	p.Lys3037Met	missense_variant	57/57	1	NM_007118.4	ENSP00000339299.4		O75962-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0505

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00443

AC:

1114

AN:

251326

Hom.:

AF XY:

0.00440

AC XY:

598

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0495

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00191

AC:

2786

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1451

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0496

Gnomad4 SAS exome

AF:

0.00330

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00382

GnomAD4 genome

AF:

0.00251

AC:

383

AN:

152324

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0504

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00217

Hom.:

Bravo

AF:

0.00239

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00409

AC:

497

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.1

N;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.33

MVP

0.53

MPC

0.40

ClinPred

0.014

GERP RS

1.9

Varity_R

0.27

gMVP

0.58

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