rs199640717

Positions:

chr22-37734669-A-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.4333A>G(p.Arg1445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,601,028 control chromosomes in the GnomAD database, including 13 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 12 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.17

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=0.003223449).

BP6

Variant 22-37734669-A-G is Benign according to our data. Variant chr22-37734669-A-G is described in ClinVar as [Benign]. Clinvar id is 43857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734669-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (327/152206) while in subpopulation AMR AF= 0.00425 (65/15296). AF 95% confidence interval is 0.00342. There are 1 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.4333A>G	p.Arg1445Gly	missense_variant	9/24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.4333A>G	p.Arg1445Gly	missense_variant	9/24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10 link	n.*3816A>G		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 link	n.*3816A>G		3_prime_UTR_variant	7/22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00296

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00175

AC:

382

AN:

217794

Hom.:

AF XY:

0.00177

AC XY:

213

AN XY:

120034

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.00242

Gnomad ASJ exome

AF:

0.00172

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000350

Gnomad FIN exome

AF:

0.000158

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00311

AC:

4511

AN:

1448822

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2201

AN XY:

719724

show subpopulations

Gnomad4 AFR exome

AF:

0.000661

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00182

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.0000779

Gnomad4 NFE exome

AF:

0.00377

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152206

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

156

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00296

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00307

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00164

AC:

ExAC

AF:

0.00141

AC:

168

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 14, 2015

p.Arg1445Gly in exon 9 of TRIOBP: This variant is not expected to have clinical significance because it is has been identified in 0.4% (122/27370) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199640717). -

TRIOBP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2021

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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.24

T;.

Polyphen

0.0060

B;B

Vest4

0.31

MVP

0.30

MPC

0.18

ClinPred

0.028

GERP RS

4.6

Varity_R

0.12

gMVP

0.19

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