Variant 8-139732009-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001160372.4(TRAPPC9):c.3249C>G(p.Phe1083Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000097 in 1,443,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. F1083F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.51

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4 linkuse as main transcript	c.3249C>G	p.Phe1083Leu	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.3249C>G	p.Phe1083Leu	missense_variant	22/23	1	NM_001160372.4	P1	Q96Q05-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000274

AC:

AN:

218814

Hom.:

AF XY:

0.0000339

AC XY:

AN XY:

117972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000157

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:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000970

AC:

AN:

1443764

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

716260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000118

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:

0.00000453

Gnomad4 OTH exome

AF:

0.0000503

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The c.3543C>G (p.F1181L) alteration is located in exon 22 (coding exon 22) of the TRAPPC9 gene. This alteration results from a C to G substitution at nucleotide position 3543, causing the phenylalanine (F) at amino acid position 1181 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1181 of the TRAPPC9 protein (p.Phe1181Leu). This variant is present in population databases (rs112551069, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TRAPPC9-related conditions. 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.030

T;T;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.022

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

Polyphen

0.68

P;P;B;P

Vest4

0.95, 0.92

MutPred

0.72

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.18

MPC

0.41

ClinPred

0.10

GERP RS

0.40

Varity_R

0.12

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.40

Position offset: 0

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