rs150947392

Positions:

• chr22-37757692-G-A
• chr22-37757692-G-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.5767G>A​(p.Ala1923Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,585,030 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1923E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.261

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=0.005015224).
• BP6: Variant 22-37757692-G-A is Benign according to our data. Variant chr22-37757692-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37757692-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000498 (713/1432700) while in subpopulation MID AF= 0.00523 (30/5736). AF 95% confidence interval is 0.00376. There are 6 homozygotes in gnomad4_exome. There are 423 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.5767G>A	p.Ala1923Thr	missense_variant	16/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.628G>A	p.Ala210Thr	missense_variant	6/14
TRIOBP	NM_138632.2	c.628G>A	p.Ala210Thr	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5767G>A	p.Ala1923Thr	missense_variant	16/24		NM_001039141.3	A2

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000915 AC: 179 AN: 195726 Hom.: 5 AF XY: 0.000981 AC XY: 104 AN XY: 105978

Gnomad AFR exome AF: 0.000175

Gnomad AMR exome AF: 0.000447

Gnomad ASJ exome AF: 0.00839

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.0000616

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000498 AC: 713 AN: 1432700 Hom.: 6 Cov.: 32 AF XY: 0.000596 AC XY: 423 AN XY: 710128

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000446

Gnomad4 ASJ exome AF: 0.00799

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000268

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74490

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000920 Hom.: 0

Bravo AF: 0.000722

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000816 AC: 7

ExAC AF: 0.000550 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TRIOBP: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	This variant is associated with the following publications: (PMID: 29197352, 28089734, 26969326) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 06, 2017

p.Ala1923Thr in exon 16 of TRIOBP: This variant is not expected to have clinica l significance because it has been identified in 0.8% (75/9030) of Ashkenazi Jew ish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs150947392). In addition, it is not conserved across specie s, including mammals. Of note, bushbaby, mouse, rat, kangaroo rat, and sloth hav e a threonine (Thr) at this position despite high nearby amino acid conservation . -

TRIOBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.1
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T;T;.;.;.;T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.38	N;.;N;N;.;N;N
REVEL	Benign	0.016
Sift	Benign	0.62	T;.;T;T;.;T;T
Sift4G	Benign	0.58	T;.;T;T;.;T;T
Polyphen		0.0050	B;B;.;.;.;.;.
Vest4		0.056
MVP		0.23
MPC		0.11
ClinPred		0.00038	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150947392; hg19: chr22-38153699;