rs34066624

chr22-37733381-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):c.4031G>A(p.Arg1344Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00365 in 1,551,186 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 6.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008185834).
• BP6: Variant 22-37733381-G-A is Benign according to our data. Variant chr22-37733381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37733381-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00228 (348/152334) while in subpopulation NFE AF= 0.0036 (245/68024). AF 95% confidence interval is 0.00323. There are 1 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.4031G>A	p.Arg1344Gln	missense_variant	8/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4031G>A	p.Arg1344Gln	missense_variant	8/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*3514G>A		3_prime_UTR_variant, NMD_transcript_variant	6/22	2

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00251 AC: 389 AN: 155072 Hom.: 2 AF XY: 0.00241 AC XY: 199 AN XY: 82546

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00825

Gnomad EAS exome AF: 0.0000915

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.000935

Gnomad NFE exome AF: 0.00399

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00380 AC: 5316 AN: 1398852 Hom.: 16 Cov.: 34 AF XY: 0.00368 AC XY: 2541 AN XY: 689990

Gnomad4 AFR exome AF: 0.000728

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00814

Gnomad4 EAS exome AF: 0.0000559

Gnomad4 SAS exome AF: 0.000669

Gnomad4 FIN exome AF: 0.000808

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00228 AC: 348 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74488

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00406 Hom.: 5

Bravo AF: 0.00250

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000516 AC: 2

ESP6500EA AF: 0.00377 AC: 30

ExAC AF: 0.00122 AC: 110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TRIOBP: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2020	- -

Autosomal recessive nonsyndromic hearing loss 28 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 03, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Arg1344Gln in Exon 08 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (30/6466) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs34066624). -

TRIOBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Deafness Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.042	T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.55	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.10	T;.
Polyphen		1.0	D;D
Vest4		0.24
MVP		0.57
MPC		0.39
ClinPred		0.037	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34066624; hg19: chr22-38129388; COSMIC: COSV105234493;