rs397516554

Positions:

chr22-37757932-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001039141.3(TRIOBP):c.6007G>A(p.Gly2003Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,556,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.23

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034212887).

BP6

Variant 22-37757932-G-A is Benign according to our data. Variant chr22-37757932-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43863.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr22-37757932-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 linkuse as main transcript	c.6007G>A	p.Gly2003Ser	missense_variant	16/24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1
TRIOBP	NM_007032.5 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	6/14		NP_008963.3	Q9H2D6-7
TRIOBP	NM_138632.2 linkuse as main transcript	c.868G>A	p.Gly290Ser	missense_variant	6/8		NP_619538.2	Q9H2D6-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1 linkuse as main transcript	c.6007G>A	p.Gly2003Ser	missense_variant	16/24		NM_001039141.3	ENSP00000496394.1		Q9H2D6-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000435

AC:

AN:

160834

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

85846

show subpopulations

Gnomad AFR exome

AF:

0.000472

Gnomad AMR exome

AF:

0.00

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:

0.0000472

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1403820

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

693108

show subpopulations

Gnomad4 AFR exome

AF:

0.000252

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000185

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000197

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 10, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2003 of the TRIOBP protein (p.Gly2003Ser). This variant is present in population databases (rs397516554, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 43863). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.6007G>A (p.G2003S) alteration is located in exon 16 (coding exon 14) of the TRIOBP gene. This alteration results from a G to A substitution at nucleotide position 6007, causing the glycine (G) at amino acid position 2003 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2013

Gly2003Ser in exon 16 of TRIOBP: This variant is not expected to have clinical significance because glycine (Gly) at position 2003 is not conserved across mamm als and several species, including pika and opposum, carry a serine (Ser) at th is position. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

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

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.034

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.8

N;.;D;D;.;D;D

REVEL

Benign

0.055

Sift

Uncertain

0.012

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

Sift4G

Benign

0.22

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

Polyphen

0.39

B;B;.;.;.;.;.

Vest4

0.23

MVP

0.38

MPC

0.26

ClinPred

0.035

GERP RS

3.3

Varity_R

0.11

gMVP

0.36

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

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