rs12484441

Positions:

• chr22-37701352-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039141.3(TRIOBP):​c.-14C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,601,948 control chromosomes in the GnomAD database, including 42,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3219 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39275 hom.)
• Consequence: TRIOBP NM_001039141.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.170

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 (BayesDel_noAF=-0.81).
• BP6: Variant 22-37701352-C-G is Benign according to our data. Variant chr22-37701352-C-G is described in ClinVar as [Benign]. Clinvar id is 43848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37701352-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.-14C>G		5_prime_UTR_variant	3/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.-14C>G		5_prime_UTR_variant	3/24		NM_001039141.3	A2
TRIOBP	ENST00000492485.5	n.123C>G		non_coding_transcript_exon_variant	2/5	1
TRIOBP	ENST00000344404.10	c.-14C>G		5_prime_UTR_variant, NMD_transcript_variant	2/22	2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28536 AN: 151988 Hom.: 3221 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.210

GnomAD3 exomes AF: 0.232 AC: 55612 AN: 240224 Hom.: 6802 AF XY: 0.239 AC XY: 31071 AN XY: 129782

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.306

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.229 AC: 331487 AN: 1449842 Hom.: 39275 Cov.: 29 AF XY: 0.232 AC XY: 167148 AN XY: 720930

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.188 AC: 28542 AN: 152106 Hom.: 3219 Cov.: 32 AF XY: 0.191 AC XY: 14230 AN XY: 74330

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.211

Alfa AF: 0.229 Hom.: 769

Bravo AF: 0.172

Asia WGS AF: 0.242 AC: 843 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	-14C>G in Exon 03 of TRIOBP: This variant is not expected to have clinical signi ficance because it has been identified in 23.2% (1567/6740) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washi -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12484441; hg19: chr22-38097359; COSMIC: COSV60376162;