rs111768745

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001160372.4(TRAPPC9):c.3149G>A(p.Arg1050Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,606,834 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1050W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00098 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 7 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

Conservation

PhyloP100: 2.54

Variant links:

Genes affected

TRAPPC9 (HGNC:30832): (trafficking protein particle complex subunit 9) This gene encodes a protein that likely plays a role in NF-kappa-B signaling. Mutations in this gene have been associated with autosomal-recessive cognitive disability. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

TRAPPC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01266858).

BP6

Variant 8-139732109-C-T is Benign according to our data. Variant chr8-139732109-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 362064.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000978 (149/152320) while in subpopulation NFE AF= 0.00184 (125/68026). AF 95% confidence interval is 0.00158. There are 2 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4 linkuse as main transcript	c.3149G>A	p.Arg1050Gln	missense_variant	22/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4 linkuse as main transcript	c.3149G>A	p.Arg1050Gln	missense_variant	22/23	1	NM_001160372.4	P1	Q96Q05-1

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000860

AC:

201

AN:

233732

Hom.:

AF XY:

0.000859

AC XY:

109

AN XY:

126950

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.0000901

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000519

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.00197

AC:

2859

AN:

1454514

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1335

AN XY:

722930

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000682

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000115

Gnomad4 NFE exome

AF:

0.00252

Gnomad4 OTH exome

AF:

0.000866

GnomAD4 genome

AF:

0.000978

AC:

149

AN:

152320

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000819

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 24, 2019	- -

Intellectual disability, autosomal recessive 13

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 13, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 13, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2018

The p.R1148Q variant (also known as c.3443G>A), located in coding exon 22 of the TRAPPC9 gene, results from a G to A substitution at nucleotide position 3443. The arginine at codon 1148 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Intellectual Disability, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.012

T;T;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.0086

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

N;N;.;N

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Benign

0.29

Polyphen

0.88

P;P;B;P

Vest4

0.37, 0.37

MVP

0.13

MPC

0.081

ClinPred

0.022

GERP RS

3.4

Varity_R

0.034

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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