rs147273930

Positions:

chr22-37751827-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2PP3BP6_Very_StrongBS1

The NM_001039141.3(TRIOBP):c.5378A>C(p.Glu1793Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000223 in 1,599,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

TRIOBP
NM_001039141.3 missense, splice_region

Scores

Splicing: ADA: 0.9905

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.85

Variant links:

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]

TRIOBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 22-37751827-A-C is Benign according to our data. Variant chr22-37751827-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 228035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37751827-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00122 (182/149676) while in subpopulation AFR AF= 0.00439 (178/40532). AF 95% confidence interval is 0.00386. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRIOBP	NM_001039141.3 linkuse as main transcript	c.5378A>C	p.Glu1793Ala	missense_variant, splice_region_variant	12/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5 linkuse as main transcript	c.239A>C	p.Glu80Ala	missense_variant, splice_region_variant	2/14		NP_008963.3
TRIOBP	NM_138632.2 linkuse as main transcript	c.239A>C	p.Glu80Ala	missense_variant, splice_region_variant	2/8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.5378A>C	p.Glu1793Ala	missense_variant, splice_region_variant	12/24		NM_001039141.3	ENSP00000496394	A2	Q9H2D6-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

176

AN:

149558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00426

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000485

GnomAD3 exomes

AF:

0.000307

AC:

AN:

250986

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00431

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000120

AC:

174

AN:

1449804

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

720892

show subpopulations

Gnomad4 AFR exome

AF:

0.00425

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.000353

GnomAD4 genome

AF:

0.00122

AC:

182

AN:

149676

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

72944

show subpopulations

Gnomad4 AFR

AF:

0.00439

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000211

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.00146

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 17, 2015	p.Glu1793Ala in exon 12 of TRIOBP: This variant is not expected to have clinical significance because it has been identified in 0.4% (45/10334) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs147273930). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2018	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.;.;.;D;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

.;T;.;T;T;T;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.0060

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.3

L;L;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;.;D;D;.;D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;.;D;D;.;D;D;D

Sift4G

Uncertain

0.0050

D;.;D;D;.;D;D;D

Polyphen

1.0

D;D;.;.;.;.;.;.

Vest4

0.55

MVP

0.54

MPC

0.57

ClinPred

0.052

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.36

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over