8-140451330-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001160372.4(TRAPPC9):c.44C>T(p.Thr15Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,606,662 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 (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.86

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 was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23809028).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000387 (59/152334) while in subpopulation AFR AF = 0.00106 (44/41572). AF 95% confidence interval is 0.000809. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4 link	c.44C>T	p.Thr15Met	missense_variant	Exon 2 of 23	ENST00000438773.4	NP_001153844.1	Q96Q05-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000438773.4 link	c.44C>T	p.Thr15Met	missense_variant	Exon 2 of 23	1	NM_001160372.4	ENSP00000405060.3		Q96Q05-1
TRAPPC9	ENST00000648948.2 link	c.44C>T	p.Thr15Met	missense_variant	Exon 2 of 23			ENSP00000498020.1		Q96Q05-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000768

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000174

AC:

AN:

241372

AF XY:

0.000182

show subpopulations

Gnomad AFR exome

AF:

0.000714

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000328

Gnomad FIN exome

AF:

0.0000587

Gnomad NFE exome

AF:

0.000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

273

AN:

1454328

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

120

AN XY:

723700

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.000224

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86246

Gnomad4 FIN exome

AF:

0.0000217

AC:

AN:

45980

Gnomad4 NFE exome

AF:

0.000196

AC:

218

AN:

1111960

Gnomad4 Remaining exome

AF:

0.000166

AC:

AN:

60338

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000387

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00106

AC:

0.0010584

AN:

0.0010584

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000770

AC:

0.000770119

AN:

0.000770119

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.0000942

AC:

0.0000941797

AN:

0.0000941797

Gnomad4 NFE

AF:

0.000132

AC:

0.000132295

AN:

0.000132295

Gnomad4 OTH

AF:

0.000473

AC:

0.00047259

AN:

0.00047259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.000416

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 113 of the TRAPPC9 protein (p.Thr113Met). This variant is present in population databases (rs142839408, gnomAD 0.1%). This missense change has been observed in individual(s) with TRAPPC9-related conditions (PMID: 35042660). ClinVar contains an entry for this variant (Variation ID: 212430). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Jun 05, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as c.44 C>T p.(Thr15Met) due to alternate nomenclature with a second TRAPPC9 variant, phase unknown, in a patient with intellectual disability, speech delay, truncal obesity, and stereotypic movements (Radenkovic et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35042660) -

not specified

Uncertain:1

Jun 17, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.338C>T (p.T113M) alteration is located in exon 2 (coding exon 2) of the TRAPPC9 gene. This alteration results from a C to T substitution at nucleotide position 338, causing the threonine (T) at amino acid position 113 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T;.;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.9

L;L;.;L

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.1

.;N;N;.

REVEL

Benign

0.26

Sift

Uncertain

0.016

.;D;D;.

Sift4G

Uncertain

0.015

.;D;D;.

Polyphen

1.0

D;D;D;D

Vest4

0.84, 0.86

MVP

0.38

MPC

1.4

ClinPred

0.081

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.58

Mutation Taster

=56/44

polymorphism

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