NM_001039141.3:c.6736G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001039141.3(TRIOBP):c.6736G>A(p.Glu2246Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00695 in 1,609,952 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 47 hom. )

Consequence

TRIOBP
NM_001039141.3 missense, splice_region

Scores

Splicing: ADA: 0.9994

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.65

Publications

14 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 22-37769262-G-A is Benign according to our data. Variant chr22-37769262-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00472 (719/152374) while in subpopulation NFE AF = 0.007 (476/68028). AF 95% confidence interval is 0.00648. There are 5 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.6736G>A	p.Glu2246Lys	missense_variant, splice_region_variant	Exon 21 of 24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1
TRIOBP	NM_007032.5 link	c.1597G>A	p.Glu533Lys	missense_variant, splice_region_variant	Exon 11 of 14		NP_008963.3	Q9H2D6-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.6736G>A	p.Glu2246Lys	missense_variant, splice_region_variant	Exon 21 of 24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000403663.6 link	c.1597G>A	p.Glu533Lys	missense_variant, splice_region_variant	Exon 11 of 14	1		ENSP00000386026.2	Q9H2D6-7
TRIOBP	ENST00000344404.10 link	n.*6219G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 19 of 22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 link	n.*6219G>A		3_prime_UTR_variant	Exon 19 of 22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

719

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00700

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00532

AC:

1273

AN:

239260

AF XY:

0.00526

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00214

Gnomad NFE exome

AF:

0.00765

Gnomad OTH exome

AF:

0.00770

GnomAD4 exome

AF:

0.00719

AC:

10478

AN:

1457578

Hom.:

Cov.:

AF XY:

0.00699

AC XY:

5067

AN XY:

724886

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

33330

American (AMR)

AF:

0.00545

AC:

242

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

422

AN:

26056

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39440

South Asian (SAS)

AF:

0.000981

AC:

AN:

85608

European-Finnish (FIN)

AF:

0.00171

AC:

AN:

52172

Middle Eastern (MID)

AF:

0.00749

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00820

AC:

9109

AN:

1110620

Other (OTH)

AF:

0.00733

AC:

441

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

666

1333

1999

2666

3332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00472

AC:

719

AN:

152374

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41594

American (AMR)

AF:

0.00529

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00700

AC:

476

AN:

68028

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

118

157

196

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:

0.00643

Hom.:

Bravo

AF:

0.00524

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00173

AC:

ESP6500EA

AF:

0.00564

AC:

ExAC

AF:

0.00490

AC:

592

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TRIOBP c.6736G>A (p.Glu2246Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. Several computational tools predict a significant impact on normal splicing: One predict the variant strengthens a cryptic 3' acceptor site. One predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0053 in 239260 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in TRIOBP causing Autosomal Recessive Nonsyndromic Hearing Loss 28 phenotype. c.6736G>A has been observed in individual(s) affected with Autosomal Recessive non-syndromic hearing loss (Sloan-Heggen_2016) and microcephaly (Grange_2022) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Nonsyndromic Hearing Loss 28. The following publications have been ascertained in the context of this evaluation (PMID: 26969326, 30872718, 36333305). ClinVar contains an entry for this variant (Variation ID: 165614). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glu2246Lys in Exon 21 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (37/6742) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs138139146). -

Feb 09, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 18, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26969326, 28089734, 29197352) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIOBP: PP3, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

5.6

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.0050

D;.;D

Polyphen

1.0

D;D;.

Vest4

0.84

MVP

0.55

MPC

0.58

ClinPred

0.017

GERP RS

4.4

Varity_R

0.37

gMVP

0.20

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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