rs200493962

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001039141.3(TRIOBP):c.5224C>T(p.Leu1742Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,571,342 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.215

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:

LOC124905115 (HGNC:):

LOC124905115 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052627325).

BP6

Variant 22-37740934-C-T is Benign according to our data. Variant chr22-37740934-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43859.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr22-37740934-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00122 (186/152356) while in subpopulation AMR AF= 0.00255 (39/15308). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3 linkuse as main transcript	c.5224C>T	p.Leu1742Phe	missense_variant	11/24	ENST00000644935.1
LOC124905115	XM_047441691.1 linkuse as main transcript	c.19-175G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.5224C>T	p.Leu1742Phe	missense_variant	11/24		NM_001039141.3	A2	Q9H2D6-1
TRIOBP	ENST00000344404.10 linkuse as main transcript	c.*4707C>T		3_prime_UTR_variant, NMD_transcript_variant	9/22	2

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00122

AC:

215

AN:

176058

Hom.:

AF XY:

0.00114

AC XY:

108

AN XY:

94324

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.00264

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000829

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00127

GnomAD4 exome

AF:

0.00119

AC:

1693

AN:

1418986

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

836

AN XY:

701544

show subpopulations

Gnomad4 AFR exome

AF:

0.000213

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00277

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000620

Gnomad4 FIN exome

AF:

0.0000595

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.00148

GnomAD4 genome

AF:

0.00122

AC:

186

AN:

152356

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000518

AC:

ESP6500EA

AF:

0.000854

AC:

ExAC

AF:

0.000858

AC:

101

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 16385458, 16385457, 27344577, 24853665) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRIOBP: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2017

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2013

p.Leu1742Phe in exon 11 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, the hedgehog, bushbaby and lesser Egyptian jerboa have a phenylalanine ( Phe) at this position despite high nearby amino acid conservation. In addition, this variant has been identified in 0.3% (37/11400) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 00493962). -

TRIOBP-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2022

This variant is classified as likely 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

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.068

M_CAP

Benign

0.0038

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.99

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.86

N;.

REVEL

Benign

0.032

Sift

Uncertain

0.012

D;.

Sift4G

Benign

0.10

T;.

Polyphen

0.22

B;B

Vest4

0.25

MVP

0.28

MPC

0.13

ClinPred

0.0048

GERP RS

1.5

Varity_R

0.068

gMVP

0.057

Splicing

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