rs7284476

chr22-37733325-G-Achr22-37733325-G-C

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.3975G>A(p.Gln1325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,550,746 control chromosomes in the GnomAD database, including 144,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10845 hom., cov: 33)
  • Exomes 𝑓: 0.43 (133426 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.43

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=-0.41).
• BP6: Variant 22-37733325-G-A is Benign according to our data. Variant chr22-37733325-G-A is described in ClinVar as [Benign]. Clinvar id is 43851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37733325-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.3975G>A	p.Gln1325=	synonymous_variant	8/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.3975G>A	p.Gln1325=	synonymous_variant	8/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*3458G>A		3_prime_UTR_variant, NMD_transcript_variant	6/22	2

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54479 AN: 151978 Hom.: 10841 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.395 AC: 61023 AN: 154642 Hom.: 12636 AF XY: 0.393 AC XY: 32394 AN XY: 82330

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.601

Gnomad SAS exome AF: 0.351

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.435

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.432 AC: 604605 AN: 1398648 Hom.: 133426 Cov.: 48 AF XY: 0.429 AC XY: 296215 AN XY: 689918

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.555

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.358 AC: 54495 AN: 152098 Hom.: 10845 Cov.: 33 AF XY: 0.355 AC XY: 26396 AN XY: 74344

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.444

Gnomad4 OTH AF: 0.349

Alfa AF: 0.414 Hom.: 27310

Bravo AF: 0.350

Asia WGS AF: 0.434 AC: 1511 AN: 3478

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gln1325Gln in Exon 08 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 43.7% (2800/6406) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7284476). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Autosomal recessive nonsyndromic hearing loss 28 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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	-0.41
Cadd	Benign	6.7
Dann	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7284476; hg19: chr22-38129332; COSMIC: COSV60378278;