Genetic Variant TRAPPC9:p.Val1081Phe (chr8-139732017-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001160372.4(TRAPPC9):c.3241G>T(p.Val1081Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1081I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TRAPPC9
NM_001160372.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.619

Publications

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

TRAPPC9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3273908).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160372.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC9	NM_001160372.4	MANE Select	c.3241G>T	p.Val1081Phe	missense	Exon 22 of 23	NP_001153844.1	Q96Q05-1
TRAPPC9	NM_001374682.1		c.3262G>T	p.Val1088Phe	missense	Exon 23 of 24	NP_001361611.1
TRAPPC9	NM_031466.8		c.3241G>T	p.Val1081Phe	missense	Exon 22 of 23	NP_113654.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAPPC9	ENST00000438773.4	TSL:1 MANE Select	c.3241G>T	p.Val1081Phe	missense	Exon 22 of 23	ENSP00000405060.3	Q96Q05-1
TRAPPC9	ENST00000520857.5	TSL:1	c.2770G>T	p.Val924Phe	missense	Exon 20 of 21	ENSP00000430116.1	H0YBR0
TRAPPC9	ENST00000521667.5	TSL:1	n.1646G>T		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446670

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33222

American (AMR)

AF:

0.00

AC:

AN:

42792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.0000256

AC:

AN:

38994

South Asian (SAS)

AF:

0.00

AC:

AN:

83590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104642

Other (OTH)

AF:

0.00

AC:

AN:

59792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.0068

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.85

M_CAP

Benign

0.028

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PhyloP100

0.62

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.17

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.017

Polyphen

0.93

Vest4

0.82

MutPred

0.49

Loss of sheet (P = 0.0457)

MVP

0.081

MPC

0.22

ClinPred

0.94

GERP RS

-4.0

Varity_R

0.38

gMVP

0.85

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over