rs61737841

Positions:

chr22-37771699-T-C

Variant summary

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

The NM_001039141.3(TRIOBP):c.6899T>C(p.Val2300Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,613,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 20 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.75

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=0.0063397586).

BP6

Variant 22-37771699-T-C is Benign according to our data. Variant chr22-37771699-T-C is described in ClinVar as [Benign]. Clinvar id is 43867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37771699-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00678 (1031/152144) while in subpopulation AFR AF= 0.0232 (963/41496). AF 95% confidence interval is 0.022. There are 12 homozygotes in gnomad4. There are 509 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3 linkuse as main transcript	c.6899T>C	p.Val2300Ala	missense_variant	22/24	ENST00000644935.1
TRIOBP	NM_007032.5 linkuse as main transcript	c.1760T>C	p.Val587Ala	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.6899T>C	p.Val2300Ala	missense_variant	22/24		NM_001039141.3	A2	Q9H2D6-1
TRIOBP	ENST00000403663.6 linkuse as main transcript	c.1760T>C	p.Val587Ala	missense_variant	12/14	1		P2	Q9H2D6-7
TRIOBP	ENST00000344404.10 linkuse as main transcript	c.*6382T>C		3_prime_UTR_variant, NMD_transcript_variant	20/22	2

Frequencies

GnomAD3 genomes

AF:

0.00674

AC:

1024

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00159

AC:

398

AN:

249572

Hom.:

AF XY:

0.00117

AC XY:

159

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000729

AC:

1065

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

439

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0243

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00678

AC:

1031

AN:

152144

Hom.:

Cov.:

AF XY:

0.00684

AC XY:

509

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0232

Gnomad4 AMR

AF:

0.00308

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.00762

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00184

AC:

223

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Val2300Ala in Exon 22 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.8% (60/3292) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61737841). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

D;.;D

REVEL

Benign

0.099

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0030

D;.;T

Polyphen

1.0

D;D;.

Vest4

0.42

MVP

0.43

MPC

0.16

ClinPred

0.025

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.37

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