11-119018919-C-G

Variant names:

• chr11-119018919-C-G
• NM_016146.6:c.124C>G

Variant summary

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

The NM_016146.6(TRAPPC4):​c.124C>G​(p.Leu42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAPPC4 NM_016146.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

Genes affected

TRAPPC4 (HGNC:19943): (trafficking protein particle complex subunit 4) Involved in autophagy and endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

RPS25 (HGNC:10413): (ribosomal protein S25) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S25E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ENSG00000283704 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
TRAPPC4	NM_016146.6	c.124C>G	p.Leu42Val	missense_variant	Exon 1 of 5	ENST00000533632.6	NP_057230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC4	ENST00000533632.6	c.124C>G	p.Leu42Val	missense_variant	Exon 1 of 5	1	NM_016146.6	ENSP00000436005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Uncertain:1

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.124C>G p.Leu42Val in the TRAPPC4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Leucine at position 42 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen, SIFT and MutationTaster predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Leu42Val in TRAPPC4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	26
DANN	Benign	0.94
DEOGEN2	Benign	0.011	T;T;T;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.51	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.14	N;.;.;N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.11	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.49	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.053
MutPred		0.61		Gain of methylation at K41 (P = 0.0525);Gain of methylation at K41 (P = 0.0525);Gain of methylation at K41 (P = 0.0525);Gain of methylation at K41 (P = 0.0525);Gain of methylation at K41 (P = 0.0525);Gain of methylation at K41 (P = 0.0525);
MVP		0.69
MPC		0.46
ClinPred		0.26	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118889629;