22-37765707-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001039141.3(TRIOBP):c.6362C>T(p.Ser2121Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000732 in 1,555,128 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2121S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (7 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.81

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007600248).
• BP6: Variant 22-37765707-C-T is Benign according to our data. Variant chr22-37765707-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165609.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000552 (84/152210) while in subpopulation SAS AF= 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 1 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6362C>T	p.Ser2121Leu	missense_variant	18/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1223C>T	p.Ser408Leu	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6362C>T	p.Ser2121Leu	missense_variant	18/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1223C>T	p.Ser408Leu	missense_variant	8/14	1		P2
TRIOBP	ENST00000344404.10	c.*5845C>T		3_prime_UTR_variant, NMD_transcript_variant	16/22	2

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152092 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00124 AC: 198 AN: 160258 Hom.: 0 AF XY: 0.00152 AC XY: 130 AN XY: 85666

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.000934

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00565

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000532

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000752 AC: 1055 AN: 1402918 Hom.: 7 Cov.: 30 AF XY: 0.000912 AC XY: 632 AN XY: 692686

Gnomad4 AFR exome AF: 0.0000943

Gnomad4 AMR exome AF: 0.000831

Gnomad4 ASJ exome AF: 0.00155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00611

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152210 Hom.: 1 Cov.: 31 AF XY: 0.000659 AC XY: 49 AN XY: 74406

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000473 AC: 4

ExAC AF: 0.000737 AC: 85

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TRIOBP: BS2 -

Autosomal recessive nonsyndromic hearing loss 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2016

p.Ser2121Leu in exon 18 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.6% (46/7960) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs201724032). -

TRIOBP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Benign	0.13
Sift	Uncertain	0.014	D;.;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.64
MVP		0.44
MPC		0.35
ClinPred		0.048	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201724032; hg19: chr22-38161714; COSMIC: COSV60384743;