rs143157673

Positions:

• chr22-37715890-C-T

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.584C>T​(p.Thr195Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,613,628 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (17 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.369

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=0.0058710277).
• BP6: Variant 22-37715890-C-T is Benign according to our data. Variant chr22-37715890-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37715890-C-T is described in Lovd as [Likely_benign]. Variant chr22-37715890-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00246 (375/152300) while in subpopulation NFE AF= 0.00422 (287/68030). AF 95% confidence interval is 0.00382. There are 0 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.584C>T	p.Thr195Ile	missense_variant	6/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.584C>T	p.Thr195Ile	missense_variant	6/24		NM_001039141.3	ENSP00000496394	A2
TRIOBP	ENST00000492485.5	n.518C>T		non_coding_transcript_exon_variant	4/5	1
TRIOBP	ENST00000344404.10	c.*67C>T		3_prime_UTR_variant, NMD_transcript_variant	4/22	2		ENSP00000340312

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00250 AC: 621 AN: 248692 Hom.: 1 AF XY: 0.00246 AC XY: 332 AN XY: 135032

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000790

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00426 AC: 6231 AN: 1461328 Hom.: 17 Cov.: 32 AF XY: 0.00412 AC XY: 2993 AN XY: 726978

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74470

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00442 Hom.: 3

Bravo AF: 0.00281

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00376 AC: 31

ExAC AF: 0.00237 AC: 286

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRIOBP: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Thr195Ile in Exon 06 of TRIOBP: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (26/6650) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143157673). -

TRIOBP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

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

Autosomal recessive nonsyndromic hearing loss 28 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.45	.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.022
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.053	T;.
Polyphen		0.14	B;B
Vest4		0.47
MVP		0.25
MPC		0.14
ClinPred		0.013	T
GERP RS		1.8
Varity_R		0.12
gMVP		0.080

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: rs143157673; hg19: chr22-38111897;