rs4821708

Positions:

• chr22-37768099-C-T

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.6498C>T​(p.Tyr2166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,611,854 control chromosomes in the GnomAD database, including 77,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5711 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71546 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.04

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-37768099-C-T is Benign according to our data. Variant chr22-37768099-C-T is described in ClinVar as [Benign]. Clinvar id is 43866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37768099-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6498C>T	p.Tyr2166=	synonymous_variant	19/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1359C>T	p.Tyr453=	synonymous_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6498C>T	p.Tyr2166=	synonymous_variant	19/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1359C>T	p.Tyr453=	synonymous_variant	9/14	1		P2
TRIOBP	ENST00000344404.10	c.*5981C>T		3_prime_UTR_variant, NMD_transcript_variant	17/22	2

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38122 AN: 151928 Hom.: 5718 Cov.: 31

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.315 AC: 77487 AN: 246366 Hom.: 12775 AF XY: 0.323 AC XY: 43132 AN XY: 133580

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.290

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.323

GnomAD4 exome AF: 0.308 AC: 449136 AN: 1459808 Hom.: 71546 Cov.: 39 AF XY: 0.312 AC XY: 226162 AN XY: 725986

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.367

Gnomad4 EAS exome AF: 0.361

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.251 AC: 38123 AN: 152046 Hom.: 5711 Cov.: 31 AF XY: 0.257 AC XY: 19069 AN XY: 74334

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.273

Alfa AF: 0.300 Hom.: 9486

Bravo AF: 0.238

Asia WGS AF: 0.354 AC: 1229 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Tyr2166Tyr in Exon 19 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 30.4% (2057/6762) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4821708). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.2
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4821708; hg19: chr22-38164106; COSMIC: COSV60377009;