rs147182402

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001160372.4(TRAPPC9):c.140G>A(p.Arg47Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000371 in 1,613,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 4.81

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10150102).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00038 (556/1461636) while in subpopulation MID AF= 0.0104 (60/5768). AF 95% confidence interval is 0.0083. There are 1 homozygotes in gnomad4_exome. There are 289 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	2/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	2/23	1	NM_001160372.4	P1	Q96Q05-1
TRAPPC9	ENST00000648948.2 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	2/23			P1	Q96Q05-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000331

AC:

AN:

251040

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000467

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000380

AC:

556

AN:

1461636

Hom.:

Cov.:

AF XY:

0.000397

AC XY:

289

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.0000940

Gnomad4 NFE exome

AF:

0.000355

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000276

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000435

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 13

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 14, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 09, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.434G>A (p.R145Q) alteration is located in exon 2 (coding exon 2) of the TRAPPC9 gene. This alteration results from a G to A substitution at nucleotide position 434, causing the arginine (R) at amino acid position 145 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, 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

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the TRAPPC9 protein (p.Arg145Gln). This variant is present in population databases (rs147182402, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with TRAPPC9-related conditions. ClinVar contains an entry for this variant (Variation ID: 362094). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.018

T;T;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.015

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;L;.;L

MutationTaster

Benign

0.86

D;D;D

PrimateAI

Uncertain

0.53

Polyphen

0.98

D;D;D;D

Vest4

0.61, 0.63

MVP

0.34

MPC

1.5

ClinPred

0.072

GERP RS

4.4

Varity_R

0.062

gMVP

0.47

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