chr22-37734669-A-G

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.4333A>G(p.Arg1445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,601,028 control chromosomes in the GnomAD database, including 13 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 12 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.17

Publications

5 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=0.003223449).

BP6

Variant 22-37734669-A-G is Benign according to our data. Variant chr22-37734669-A-G is described in ClinVar as Benign. ClinVar VariationId is 43857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00215 (327/152206) while in subpopulation AMR AF = 0.00425 (65/15296). AF 95% confidence interval is 0.00342. There are 1 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.4333A>G	p.Arg1445Gly	missense_variant	Exon 9 of 24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.4333A>G	p.Arg1445Gly	missense_variant	Exon 9 of 24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10 link	n.*3816A>G		non_coding_transcript_exon_variant	Exon 7 of 22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 link	n.*3816A>G		3_prime_UTR_variant	Exon 7 of 22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00296

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00175

AC:

382

AN:

217794

AF XY:

0.00177

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.00242

Gnomad ASJ exome

AF:

0.00172

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000158

Gnomad NFE exome

AF:

0.00280

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00311

AC:

4511

AN:

1448822

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2201

AN XY:

719724

show subpopulations

African (AFR)

AF:

0.000661

AC:

AN:

33296

American (AMR)

AF:

0.00239

AC:

101

AN:

42322

Ashkenazi Jewish (ASJ)

AF:

0.00182

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39196

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84770

European-Finnish (FIN)

AF:

0.0000779

AC:

AN:

51376

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00377

AC:

4166

AN:

1106372

Other (OTH)

AF:

0.00281

AC:

168

AN:

59886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

303

606

910

1213

1516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00215

AC:

327

AN:

152206

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

156

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41546

American (AMR)

AF:

0.00425

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00296

AC:

201

AN:

67994

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.00298

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.00164

AC:

ExAC

AF:

0.00141

AC:

168

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg1445Gly in exon 9 of TRIOBP: This variant is not expected to have clinical significance because it is has been identified in 0.4% (122/27370) of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs199640717). -

TRIOBP-related disorder

Benign:1

Aug 19, 2021

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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PhyloP100

2.2

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0020

D;.

Sift4G

Benign

0.24

T;.

Polyphen

0.0060

B;B

Vest4

0.31

MVP

0.30

MPC

0.18

ClinPred

0.028

GERP RS

4.6

Varity_R

0.12

gMVP

0.19

Mutation Taster

=92/8

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