rs140528529

chr22-37755560-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.5588C>T(p.Ala1863Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,613,978 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (14 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.37

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=0.013053089).
• BP6: Variant 22-37755560-C-T is Benign according to our data. Variant chr22-37755560-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 177980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (292/152332) while in subpopulation NFE AF= 0.00268 (182/68024). AF 95% confidence interval is 0.00236. There are 1 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.5588C>T	p.Ala1863Val	missense_variant	15/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.449C>T	p.Ala150Val	missense_variant	5/14
TRIOBP	NM_138632.2	c.449C>T	p.Ala150Val	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5588C>T	p.Ala1863Val	missense_variant	15/24		NM_001039141.3	A2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251282 Hom.: 5 AF XY: 0.00217 AC XY: 295 AN XY: 135882

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00518

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00225 AC: 3292 AN: 1461646 Hom.: 14 Cov.: 32 AF XY: 0.00226 AC XY: 1641 AN XY: 727142

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74486

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00715

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00261 Hom.: 1

Bravo AF: 0.00125

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00244 AC: 296

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TRIOBP: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 19, 2015	p.Ala1863Val in exon 15 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.33% (220/66206) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs140528529). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2017	- -

TRIOBP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.;.;D;T;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.5	L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	D;.;D;D;.;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;.;D;D;.;D;D;D
Sift4G	Uncertain	0.0070	D;.;D;D;.;D;D;D
Polyphen		0.98	D;D;.;.;.;.;.;.
Vest4		0.67
MVP		0.89
MPC		0.46
ClinPred		0.023	T
GERP RS		2.8
Varity_R		0.28
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs140528529; hg19: chr22-38151567; COSMIC: COSV58526407; COSMIC: COSV58526407;