chr1-36137826-C-A

Variant names:

• chr1-36137826-C-A
• rs141225393
• NM_014408.5:c.393G>T

Variant summary

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

The NM_014408.5(TRAPPC3):​c.393G>T​(p.Leu131Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,614,190 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: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: TRAPPC3 NM_014408.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.548

Genes affected

TRAPPC3 (HGNC:19942): (trafficking protein particle complex subunit 3) This gene encodes a component of the trafficking protein particle complex, which tethers transport vesicles to the cis-Golgi membrane. The encoded protein participates in the regulation of transport from the endoplasmic reticulum to the Golgi apparatus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

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=0.31444627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC3	NM_014408.5	c.393G>T	p.Leu131Phe	missense_variant	Exon 4 of 5	ENST00000373166.8	NP_055223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC3	ENST00000373166.8	c.393G>T	p.Leu131Phe	missense_variant	Exon 4 of 5	1	NM_014408.5	ENSP00000362261.3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251428 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135892

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.000287 AC XY: 209 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152316 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 139 of the TRAPPC3 protein (p.Leu139Phe). This variant is present in population databases (rs141225393, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TRAPPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1417400). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;.;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	.;.;.;M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	.;.;.;D;D;D
REVEL	Uncertain	0.29
Sift	Benign	0.092	.;.;.;T;T;T
Sift4G	Benign	0.079	T;T;.;T;.;.
Polyphen		0.69	.;.;.;P;.;.
Vest4		0.82
MutPred		0.71		.;.;.;Loss of catalytic residue at L131 (P = 0.0141);.;.;
MVP		0.55
MPC		1.1
ClinPred		0.098	T
GERP RS		3.8
Varity_R		0.74
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs141225393; hg19: chr1-36603427;