6-116500533-G-A

Position:

• chr6-116500533-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001139444.3(TRAPPC3L):​c.374C>T​(p.Ser125Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TRAPPC3L NM_001139444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

TRAPPC3L (HGNC:21090): (trafficking protein particle complex subunit 3L) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport and intra-Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36724505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC3L	NM_001139444.3	c.374C>T	p.Ser125Phe	missense_variant	4/5	ENST00000368602.4	NP_001132916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC3L	ENST00000368602.4	c.374C>T	p.Ser125Phe	missense_variant	4/5	5	NM_001139444.3	ENSP00000357591.3
TRAPPC3L	ENST00000437098.5	c.332C>T	p.Ser111Phe	missense_variant	3/4	3		ENSP00000395769.1
TRAPPC3L	ENST00000356128.4	c.122C>T	p.Ser41Phe	missense_variant	2/3	2		ENSP00000348445.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399262 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.374C>T (p.S125F) alteration is located in exon 4 (coding exon 4) of the TRAPPC3L gene. This alteration results from a C to T substitution at nucleotide position 374, causing the serine (S) at amino acid position 125 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.057
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.68	.;.;P
Vest4		0.23
MutPred		0.28		.;.;Gain of sheet (P = 0.0344);
MVP		0.15
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.42
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs898564008; hg19: chr6-116821696;