22-37765707-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.6362C>T(p.Ser2121Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000732 in 1,555,128 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2121S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00075 ( 7 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.81

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007600248).

BP6

Variant 22-37765707-C-T is Benign according to our data. Variant chr22-37765707-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165609.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000552 (84/152210) while in subpopulation SAS AF = 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.6362C>T	p.Ser2121Leu	missense_variant	Exon 18 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5 link	c.1223C>T	p.Ser408Leu	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.6362C>T	p.Ser2121Leu	missense_variant	Exon 18 of 24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000403663.6 link	c.1223C>T	p.Ser408Leu	missense_variant	Exon 8 of 14	1		ENSP00000386026.2
TRIOBP	ENST00000344404.10 link	n.*5845C>T		non_coding_transcript_exon_variant	Exon 16 of 22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10 link	n.*5845C>T		3_prime_UTR_variant	Exon 16 of 22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00124

AC:

198

AN:

160258

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.000119

Gnomad AMR exome

AF:

0.000638

Gnomad ASJ exome

AF:

0.000934

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000532

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000752

AC:

1055

AN:

1402918

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

632

AN XY:

692686

show subpopulations

African (AFR)

AF:

0.0000943

AC:

AN:

31806

American (AMR)

AF:

0.000831

AC:

AN:

36120

Ashkenazi Jewish (ASJ)

AF:

0.00155

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

36076

South Asian (SAS)

AF:

0.00611

AC:

486

AN:

79562

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

49122

Middle Eastern (MID)

AF:

0.00377

AC:

AN:

4778

European-Non Finnish (NFE)

AF:

0.000381

AC:

412

AN:

1082120

Other (OTH)

AF:

0.00114

AC:

AN:

58122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000552

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41528

American (AMR)

AF:

0.000721

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00560

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68026

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.000702

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000473

AC:

ExAC

AF:

0.000737

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIOBP: BS2 -

Jul 22, 2020

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 21, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Autosomal recessive nonsyndromic hearing loss 28

Uncertain:1

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser2121Leu in exon 18 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.6% (46/7960) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs201724032). -

TRIOBP-related disorder

Benign:1

Mar 10, 2020

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

0.31

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

.;D;D

MetaRNN

Benign

0.0076

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;M;.

PhyloP100

3.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.7

D;.;D

REVEL

Benign

0.13

Sift

Uncertain

0.014

D;.;D

Sift4G

Uncertain

0.0030

D;.;D

Polyphen

1.0

D;D;.

Vest4

0.64

MVP

0.44

MPC

0.35

ClinPred

0.048

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.75

Mutation Taster

=65/35

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