rs781135139

Variant names:

• chr22-37757707-A-G
• rs781135139
• NM_001039141.3:c.5782A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001039141.3(TRIOBP):​c.5782A>G​(p.Ile1928Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000063 in 1,429,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05399576).
• BP6: Variant 22-37757707-A-G is Benign according to our data. Variant chr22-37757707-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228038.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.5782A>G	p.Ile1928Val	missense_variant	Exon 16 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.643A>G	p.Ile215Val	missense_variant	Exon 6 of 14		NP_008963.3
TRIOBP	NM_138632.2	c.643A>G	p.Ile215Val	missense_variant	Exon 6 of 8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5782A>G	p.Ile1928Val	missense_variant	Exon 16 of 24		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000260 AC: 5 AN: 192090 AF XY: 0.0000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000630 AC: 9 AN: 1429594 Hom.: 0 Cov.: 32 AF XY: 0.00000424 AC XY: 3 AN XY: 708302

African (AFR) AF: 0.00 AC: 0 AN: 32804

American (AMR) AF: 0.000225 AC: 9 AN: 39916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.00 AC: 0 AN: 37952

South Asian (SAS) AF: 0.00 AC: 0 AN: 82012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097182

Other (OTH) AF: 0.00 AC: 0 AN: 59176

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000835 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1928 of the TRIOBP protein (p.Ile1928Val). This variant is present in population databases (rs781135139, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 228038). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 16, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Feb 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile1928Val in exon 16 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, Rhesus, crab-eating macaque, baboon, and green monkey have a valine (Val ) at this position. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.55
DEOGEN2	Benign	0.018	T;T;.;.;.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.58	.;T;.;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.054	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.10	N;.;N;N;.;N;N
REVEL	Benign	0.072
Sift	Benign	0.092	T;.;T;T;.;T;T
Sift4G	Benign	0.26	T;.;T;T;.;T;T
Polyphen		0.0020	B;B;.;.;.;.;.
Vest4		0.12
MutPred		0.092		Gain of MoRF binding (P = 0.116);Gain of MoRF binding (P = 0.116);.;.;.;.;.;
MVP		0.20
MPC		0.097
ClinPred		0.042	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.15
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs781135139; hg19: chr22-38153714;