chr8-139885953-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001160372.4(TRAPPC9):c.2981G>C(p.Ser994Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 1,568,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.488

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 13
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
intellectual disability-obesity-brain malformations-facial dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRAPPC9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024111569).

BP6

Variant 8-139885953-C-G is Benign according to our data. Variant chr8-139885953-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437026.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4 link	c.2981G>C	p.Ser994Thr	missense_variant	Exon 21 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.2981G>C	p.Ser994Thr	missense_variant	Exon 21 of 23	1	NM_001160372.4	ENSP00000405060.3		Q96Q05-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.0000336

AC:

AN:

178790

AF XY:

0.0000316

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000290

AC:

AN:

1416198

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

699930

show subpopulations

African (AFR)

AF:

0.000368

AC:

AN:

32594

American (AMR)

AF:

0.0000261

AC:

AN:

38286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25338

East Asian (EAS)

AF:

0.00

AC:

AN:

37560

South Asian (SAS)

AF:

0.00

AC:

AN:

80284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000211

AC:

AN:

1087742

Other (OTH)

AF:

0.0000852

AC:

AN:

58686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000138

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41584

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000712

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000597

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:2

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1092 of the TRAPPC9 protein (p.Ser1092Thr). This variant is present in population databases (rs377114410, 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: 437026). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine 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. -

Oct 04, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Jul 29, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 16, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.3

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.012

T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.58

.;.;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;N;.;N

PhyloP100

0.49

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.020

.;N;N;.

REVEL

Benign

0.044

Sift

Benign

0.68

.;T;T;.

Sift4G

Benign

0.62

.;T;T;.

Polyphen

0.0

B;B;B;B

Vest4

0.14, 0.14

MVP

0.048

MPC

0.065

ClinPred

0.0026

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.048

gMVP

0.14

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over