rs11704996

Positions:

• chr22-37755163-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001039141.3(TRIOBP):​c.5550G>A​(p.Val1850Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,613,060 control chromosomes in the GnomAD database, including 2,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (298 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2512 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.474

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-37755163-G-A is Benign according to our data. Variant chr22-37755163-G-A is described in ClinVar as [Benign]. Clinvar id is 43862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.5550G>A	p.Val1850Val	synonymous_variant	14/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.411G>A	p.Val137Val	synonymous_variant	4/14		NP_008963.3
TRIOBP	NM_138632.2	c.411G>A	p.Val137Val	synonymous_variant	4/8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5550G>A	p.Val1850Val	synonymous_variant	14/24		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9104 AN: 152134 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0967

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.0424

Gnomad SAS AF: 0.0393

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0581 AC: 14454 AN: 248862 Hom.: 500 AF XY: 0.0542 AC XY: 7299 AN XY: 134632

Gnomad AFR exome AF: 0.0520

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.0454

Gnomad SAS exome AF: 0.0329

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0558

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0567 AC: 82808 AN: 1460808 Hom.: 2512 Cov.: 34 AF XY: 0.0553 AC XY: 40199 AN XY: 726604

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.0320

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0540

Gnomad4 NFE exome AF: 0.0581

Gnomad4 OTH exome AF: 0.0568

GnomAD4 genome AF: 0.0598 AC: 9109 AN: 152252 Hom.: 298 Cov.: 32 AF XY: 0.0599 AC XY: 4460 AN XY: 74442

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.0915

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.0425

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.0572

Gnomad4 NFE AF: 0.0605

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0561 Hom.: 272

Bravo AF: 0.0599

Asia WGS AF: 0.0440 AC: 156 AN: 3478

EpiCase AF: 0.0554

EpiControl AF: 0.0488

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val1850Val in Exon 14 of TRIOBP: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 5.6% (392/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11704996). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.0
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11704996; hg19: chr22-38151170;