NM_001039141.3:c.6455C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001039141.3(TRIOBP):c.6455C>T(p.Thr2152Met) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,581,080 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2152T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 145 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.85

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033282042).

BP6

Variant 22-37765800-C-T is Benign according to our data. Variant chr22-37765800-C-T is described in ClinVar as Benign. ClinVar VariationId is 165610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00158 (225/142272) while in subpopulation SAS AF = 0.0485 (217/4474). AF 95% confidence interval is 0.0432. There are 7 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.6455C>T	p.Thr2152Met	missense_variant	Exon 18 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5 link	c.1316C>T	p.Thr439Met	missense_variant	Exon 8 of 14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRIOBP	ENST00000644935.1 link	c.6455C>T	p.Thr2152Met	missense_variant	Exon 18 of 24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000403663.6 link	c.1316C>T	p.Thr439Met	missense_variant	Exon 8 of 14	1		ENSP00000386026.2
TRIOBP	ENST00000344404.10 link	n.*5938C>T		non_coding_transcript_exon_variant	Exon 16 of 22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10 link	n.*5938C>T		3_prime_UTR_variant	Exon 16 of 22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

227

AN:

142154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000626

Gnomad SAS

AF:

0.0489

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000152

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00657

AC:

1317

AN:

200552

AF XY:

0.00881

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000968

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000226

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00294

AC:

4232

AN:

1438808

Hom.:

145

Cov.:

AF XY:

0.00427

AC XY:

3054

AN XY:

714476

show subpopulations

African (AFR)

AF:

0.0000604

AC:

AN:

33140

American (AMR)

AF:

0.0000946

AC:

AN:

42286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38766

South Asian (SAS)

AF:

0.0479

AC:

3995

AN:

83472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46614

Middle Eastern (MID)

AF:

0.00206

AC:

AN:

4860

European-Non Finnish (NFE)

AF:

0.0000254

AC:

AN:

1104352

Other (OTH)

AF:

0.00323

AC:

192

AN:

59498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

244

487

731

974

1218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00158

AC:

225

AN:

142272

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

154

AN XY:

69008

show subpopulations

African (AFR)

AF:

0.000109

AC:

AN:

36698

American (AMR)

AF:

0.00

AC:

AN:

14052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.000628

AC:

AN:

4778

South Asian (SAS)

AF:

0.0485

AC:

217

AN:

4474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65946

Other (OTH)

AF:

0.00

AC:

AN:

1936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000383

Hom.:

Bravo

AF:

0.000332

ExAC

AF:

0.00625

AC:

738

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 29, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Thr2152Met in exon 18 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 6% (617/9750) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs534215753). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TRIOBP-related disorder

Benign:1

Mar 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

.;D;D

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

5.8

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

D;.;D

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;D;.

Vest4

0.61

MVP

0.44

MPC

0.54

ClinPred

0.073

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.27

Mutation Taster

=96/4

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