rs150947392

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1923E) has been classified as Uncertain significance.

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:7

Conservation

PhyloP100: 0.261

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 28
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

TRIOBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 178559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 423 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.5767G>A	p.Ala1923Thr	missense_variant	Exon 16 of 24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1
TRIOBP	NM_007032.5 link	c.628G>A	p.Ala210Thr	missense_variant	Exon 6 of 14		NP_008963.3	Q9H2D6-7
TRIOBP	NM_138632.2 link	c.628G>A	p.Ala210Thr	missense_variant	Exon 6 of 8		NP_619538.2	Q9H2D6-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1 link	c.5767G>A	p.Ala1923Thr	missense_variant	Exon 16 of 24		NM_001039141.3	ENSP00000496394.1		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

GnomAD2 exomes

AF:

0.000915

AC:

179

AN:

195726

AF XY:

0.000981

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 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

African (AFR)

AF:

0.0000304

AC:

AN:

32870

American (AMR)

AF:

0.000446

AC:

AN:

40328

Ashkenazi Jewish (ASJ)

AF:

0.00799

AC:

204

AN:

25540

East Asian (EAS)

AF:

0.00

AC:

AN:

38164

South Asian (SAS)

AF:

0.00117

AC:

AN:

82306

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49524

Middle Eastern (MID)

AF:

0.00523

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000268

AC:

294

AN:

1098922

Other (OTH)

AF:

0.00116

AC:

AN:

59310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000650

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41582

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68006

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000839

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIOBP: BP4, BS2 -

Oct 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29197352, 28089734, 26969326) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Autosomal recessive nonsyndromic hearing loss 28

Benign:1

Jul 15, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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;.;.;.;.;.

PhyloP100

0.26

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

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over