NM_001039141.3:c.5487+9A>G

Variant names:

• chr22-37754993-A-G
• rs56016429
• NM_001039141.3:c.5487+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039141.3(TRIOBP):​c.5487+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,613,678 control chromosomes in the GnomAD database, including 1,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (170 hom., cov: 32)
  • Exomes 𝑓: 0.028 (849 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.40
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-37754993-A-G is Benign according to our data. Variant chr22-37754993-A-G is described in ClinVar as Benign. ClinVar VariationId is 43860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.5487+9A>G		intron_variant	Intron 13 of 23	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.348+9A>G		intron_variant	Intron 3 of 13		NP_008963.3
TRIOBP	NM_138632.2	c.348+9A>G		intron_variant	Intron 3 of 7		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5487+9A>G		intron_variant	Intron 13 of 23		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6185 AN: 152182 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0338 AC: 8454 AN: 250168 AF XY: 0.0353

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0328

GnomAD4 exome AF: 0.0280 AC: 40974 AN: 1461378 Hom.: 849 Cov.: 33 AF XY: 0.0295 AC XY: 21429 AN XY: 726956

African (AFR) AF: 0.0770 AC: 2576 AN: 33470

American (AMR) AF: 0.0185 AC: 828 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 1490 AN: 26118

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.0728 AC: 6273 AN: 86178

European-Finnish (FIN) AF: 0.0310 AC: 1656 AN: 53364

Middle Eastern (MID) AF: 0.0717 AC: 413 AN: 5764

European-Non Finnish (NFE) AF: 0.0232 AC: 25821 AN: 1111738

Other (OTH) AF: 0.0317 AC: 1911 AN: 60378

GnomAD4 genome AF: 0.0406 AC: 6188 AN: 152300 Hom.: 170 Cov.: 32 AF XY: 0.0413 AC XY: 3078 AN XY: 74476

African (AFR) AF: 0.0744 AC: 3093 AN: 41550

American (AMR) AF: 0.0231 AC: 354 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 193 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4822

European-Finnish (FIN) AF: 0.0347 AC: 368 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1617 AN: 68036

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0347 Hom.: 47

Bravo AF: 0.0400

Asia WGS AF: 0.0340 AC: 120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

5487+9A>G in Intron 13 of TRIOBP: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 7.2% (269/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs56016429). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 24, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2018

Athena Diagnostics

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.68
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56016429; hg19: chr22-38151000;