8-139731122-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001160372.4(TRAPPC9):āc.3386T>Cā(p.Leu1129Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
TRAPPC9
NM_001160372.4 missense
NM_001160372.4 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 8.36
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]
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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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRAPPC9 | NM_001160372.4 | c.3386T>C | p.Leu1129Pro | missense_variant | 23/23 | ENST00000438773.4 | NP_001153844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRAPPC9 | ENST00000438773.4 | c.3386T>C | p.Leu1129Pro | missense_variant | 23/23 | 1 | NM_001160372.4 | ENSP00000405060.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250560Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135714
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461628Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727116
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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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 | Mar 07, 2024 | The c.3680T>C (p.L1227P) alteration is located in exon 23 (coding exon 23) of the TRAPPC9 gene. This alteration results from a T to C substitution at nucleotide position 3680, causing the leucine (L) at amino acid position 1227 to be replaced by a proline (P). 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jun 13, 2022 | This sequence change replaces leucine with proline at codon 1227 of the TRAPPC9 protein (p.Leu1227Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;.
REVEL
Uncertain
Sift
Benign
.;T;T;.
Sift4G
Benign
.;T;T;.
Polyphen
D;D;D;D
Vest4
0.68, 0.70
MutPred
Gain of glycosylation at L1129 (P = 0.0072);Gain of glycosylation at L1129 (P = 0.0072);.;Gain of glycosylation at L1129 (P = 0.0072);
MVP
0.46
MPC
0.52
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at