chr11-119018919-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016146.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC4	NM_016146.6	MANE Select	c.124C>G	p.Leu42Val	missense	Exon 1 of 5	NP_057230.1	Q9Y296-1
	TRAPPC4	NM_001318488.2		c.124C>G	p.Leu42Val	missense	Exon 1 of 5	NP_001305417.1	J3KP27
	TRAPPC4	NM_001318490.2		c.124C>G	p.Leu42Val	missense	Exon 1 of 5	NP_001305419.1	E9PQE8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC4	ENST00000533632.6	TSL:1 MANE Select	c.124C>G	p.Leu42Val	missense	Exon 1 of 5	ENSP00000436005.1	Q9Y296-1
	TRAPPC4	ENST00000533058.5	TSL:2	c.124C>G	p.Leu42Val	missense	Exon 1 of 5	ENSP00000432920.1	E9PN70
	TRAPPC4	ENST00000359005.8	TSL:2	c.124C>G	p.Leu42Val	missense	Exon 1 of 5	ENSP00000351896.4	J3KP27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.12
Sift	Benign	0.49	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.61		Gain of methylation at K41 (P = 0.0525)
MVP		0.69
MPC		0.46
ClinPred		0.26	T
GERP RS		4.9
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.35
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

hg19: chr11-118889629;