rs199646135

Positions:

chr22-37713220-C-G

Variant summary

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

The NM_001039141.3(TRIOBP):c.265C>G(p.Pro89Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,514 control chromosomes in the GnomAD database, including 27 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 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 24 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.411

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:

ENSG00000100101 (HGNC:):

ENSG00000100101 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=0.0034452677).

BP6

Variant 22-37713220-C-G is Benign according to our data. Variant chr22-37713220-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 165582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37713220-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00377 (573/152184) while in subpopulation NFE AF= 0.0061 (415/68002). AF 95% confidence interval is 0.00562. There are 3 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.265C>G	p.Pro89Ala	missense_variant	5/24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.265C>G	p.Pro89Ala	missense_variant	5/24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
ENSG00000100101	ENST00000455236.4 link	n.*601C>G		non_coding_transcript_exon_variant	11/13	5		ENSP00000477208.1	V9GYY5
ENSG00000100101	ENST00000455236.4 link	n.*601C>G		3_prime_UTR_variant	11/13	5		ENSP00000477208.1	V9GYY5

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

574

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00439

AC:

1082

AN:

246418

Hom.:

AF XY:

0.00492

AC XY:

659

AN XY:

133954

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.00348

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00157

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00599

GnomAD4 exome

AF:

0.00470

AC:

6871

AN:

1461330

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

3402

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.000282

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.00377

AC:

573

AN:

152184

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

240

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00413

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00610

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00591

Hom.:

Bravo

AF:

0.00417

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000529

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00453

AC:

547

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0103

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TRIOBP: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Pro89Ala in Exon 05 of TRIOBP: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (54/6636) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). -

Autosomal recessive nonsyndromic hearing loss 28

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.43

.;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.041

Sift

Benign

0.041

D;.

Sift4G

Benign

0.59

T;.

Polyphen

0.020

B;B

Vest4

0.14

MVP

0.21

MPC

0.12

ClinPred

0.0029

GERP RS

-0.52

Varity_R

0.032

gMVP

0.069

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