22-37740934-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/21 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

Publications

4 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:

LOC124905115 (HGNC:):

LOC124905115 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 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 VariationId is 43859.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.5224C>T	p.Leu1742Phe	missense_variant	Exon 11 of 24	ENST00000644935.1	NP_001034230.1
LOC124905115	XM_047441691.1 link	c.19-175G>A		intron_variant	Intron 1 of 2		XP_047297647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRIOBP	ENST00000644935.1 link	c.5224C>T	p.Leu1742Phe	missense_variant	Exon 11 of 24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10 link	n.*4707C>T		non_coding_transcript_exon_variant	Exon 9 of 22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10 link	n.*4707C>T		3_prime_UTR_variant	Exon 9 of 22	2		ENSP00000340312.6

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

GnomAD2 exomes

AF:

0.00122

AC:

215

AN:

176058

AF XY:

0.00114

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 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

African (AFR)

AF:

0.000213

AC:

AN:

32918

American (AMR)

AF:

0.00259

AC:

AN:

37080

Ashkenazi Jewish (ASJ)

AF:

0.00277

AC:

AN:

25298

East Asian (EAS)

AF:

0.00

AC:

AN:

38080

South Asian (SAS)

AF:

0.0000620

AC:

AN:

80636

European-Finnish (FIN)

AF:

0.0000595

AC:

AN:

50384

Middle Eastern (MID)

AF:

0.00332

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00129

AC:

1406

AN:

1090062

Other (OTH)

AF:

0.00148

AC:

AN:

58810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

110

221

331

442

552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00122

AC:

186

AN:

152356

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41588

American (AMR)

AF:

0.00255

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00150

AC:

102

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00134

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIOBP: BP4 -

Oct 19, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16385458, 16385457, 27344577, 24853665) -

Inborn genetic diseases

Uncertain:1

Jul 21, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 30, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 27, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

PhyloP100

-0.21

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

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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