chr22-37724705-C-G

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.2149C>G(p.Gln717Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,024 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0023 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0036 ( 13 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -3.66

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:

ENSG00000100101 (HGNC:):

ENSG00000100101 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=0.0028777122).

BP6

Variant 22-37724705-C-G is Benign according to our data. Variant chr22-37724705-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286759.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00226 (342/151394) while in subpopulation NFE AF = 0.00374 (254/67892). AF 95% confidence interval is 0.00336. There are 0 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.2149C>G	p.Gln717Glu	missense_variant	Exon 7 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.2149C>G	p.Gln717Glu	missense_variant	Exon 7 of 24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
ENSG00000100101	ENST00000455236.4 link	n.*2485C>G		non_coding_transcript_exon_variant	Exon 13 of 13	5		ENSP00000477208.1	V9GYY5
ENSG00000100101	ENST00000455236.4 link	n.*2485C>G		3_prime_UTR_variant	Exon 13 of 13	5		ENSP00000477208.1	V9GYY5

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

342

AN:

151268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000708

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000285

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00374

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00219

AC:

547

AN:

249568

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00343

Gnomad OTH exome

AF:

0.00198

GnomAD4 exome

AF:

0.00358

AC:

5232

AN:

1461630

Hom.:

Cov.:

150

AF XY:

0.00339

AC XY:

2468

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33468

American (AMR)

AF:

0.000448

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

319

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.000174

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00423

AC:

4702

AN:

1111906

Other (OTH)

AF:

0.00255

AC:

154

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

397

795

1192

1590

1987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00226

AC:

342

AN:

151394

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

172

AN XY:

74012

show subpopulations

African (AFR)

AF:

0.000706

AC:

AN:

41096

American (AMR)

AF:

0.00112

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00374

AC:

254

AN:

67892

Other (OTH)

AF:

0.00190

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00346

Hom.:

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00128

AC:

ESP6500EA

AF:

0.00458

AC:

ExAC

AF:

0.00200

AC:

242

EpiCase

AF:

0.00273

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Q717E variant in the TRIOBP gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The XX variant is observed in 232/66734 (0.35%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The Q717E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret Q717E as a variant of uncertain significance. -

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 28

Uncertain:1Benign:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.64

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.020

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.18

.;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;L

PhyloP100

-3.7

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.58

N;.

REVEL

Benign

0.017

Sift

Benign

0.067

T;.

Sift4G

Benign

0.33

T;.

Polyphen

0.0030

B;B

Vest4

0.10

MVP

0.15

MPC

0.13

ClinPred

0.013

GERP RS

-9.1

Varity_R

0.065

gMVP

0.013

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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chr22-37724705-C-G

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