rs150947392

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001039141.3(TRIOBP):c.5767G>A(p.Ala1923Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,585,030 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 6 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.261

Variant links:

Genes affected

TRIOBP (HGNC:17009): (TRIO and F-actin binding protein) This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]

TRIOBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005015224).

BP6

Variant 22-37757692-G-A is Benign according to our data. Variant chr22-37757692-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37757692-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000498 (713/1432700) while in subpopulation MID AF= 0.00523 (30/5736). AF 95% confidence interval is 0.00376. There are 6 homozygotes in gnomad4_exome. There are 423 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRIOBP	NM_001039141.3 linkuse as main transcript	c.5767G>A	p.Ala1923Thr	missense_variant	16/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5 linkuse as main transcript	c.628G>A	p.Ala210Thr	missense_variant	6/14		NP_008963.3
TRIOBP	NM_138632.2 linkuse as main transcript	c.628G>A	p.Ala210Thr	missense_variant	6/8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.5767G>A	p.Ala1923Thr	missense_variant	16/24		NM_001039141.3	ENSP00000496394	A2	Q9H2D6-1

Frequencies

GnomAD3 genomes

AF:

0.000650

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000915

AC:

179

AN:

195726

Hom.:

AF XY:

0.000981

AC XY:

104

AN XY:

105978

show subpopulations

Gnomad AFR exome

AF:

0.000175

Gnomad AMR exome

AF:

0.000447

Gnomad ASJ exome

AF:

0.00839

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00128

Gnomad FIN exome

AF:

0.0000616

Gnomad NFE exome

AF:

0.000534

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.000498

AC:

713

AN:

1432700

Hom.:

Cov.:

AF XY:

0.000596

AC XY:

423

AN XY:

710128

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.000446

Gnomad4 ASJ exome

AF:

0.00799

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00117

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.000268

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000650

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000920

Hom.:

Bravo

AF:

0.000722

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000816

AC:

ExAC

AF:

0.000550

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	Nov 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	This variant is associated with the following publications: (PMID: 29197352, 28089734, 26969326) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TRIOBP: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 06, 2017

p.Ala1923Thr in exon 16 of TRIOBP: This variant is not expected to have clinica l significance because it has been identified in 0.8% (75/9030) of Ashkenazi Jew ish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs150947392). In addition, it is not conserved across specie s, including mammals. Of note, bushbaby, mouse, rat, kangaroo rat, and sloth hav e a threonine (Thr) at this position despite high nearby amino acid conservation . -

TRIOBP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.1

DANN

Benign

0.86

DEOGEN2

Benign

0.011

T;T;.;.;.;T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.69

.;T;.;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0050

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.38

N;.;N;N;.;N;N

REVEL

Benign

0.016

Sift

Benign

0.62

T;.;T;T;.;T;T

Sift4G

Benign

0.58

T;.;T;T;.;T;T

Polyphen

0.0050

B;B;.;.;.;.;.

Vest4

0.056

MVP

0.23

MPC

0.11

ClinPred

0.00038

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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