19-7682470-G-A

Variant names:

• chr19-7682470-G-A
• rs2032658030
• NM_001042462.2:c.217G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042462.2(TRAPPC5):​c.217G>A​(p.Glu73Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TRAPPC5 NM_001042462.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12

Genes affected

TRAPPC5 (HGNC:23067): (trafficking protein particle complex subunit 5) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269711 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC5	NM_001042462.2	c.217G>A	p.Glu73Lys	missense_variant	Exon 2 of 2	ENST00000596148.3	NP_001035927.1
TRAPPC5	NM_001042461.3	c.217G>A	p.Glu73Lys	missense_variant	Exon 2 of 2		NP_001035926.1
TRAPPC5	NM_174894.3	c.217G>A	p.Glu73Lys	missense_variant	Exon 2 of 2		NP_777554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC5	ENST00000596148.3	c.217G>A	p.Glu73Lys	missense_variant	Exon 2 of 2	1	NM_001042462.2	ENSP00000470262.1
ENSG00000269711	ENST00000597959.1	c.392G>A	p.Arg131Gln	missense_variant	Exon 3 of 3	4		ENSP00000469811.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458094 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725094

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217G>A (p.E73K) alteration is located in exon 2 (coding exon 1) of the TRAPPC5 gene. This alteration results from a G to A substitution at nucleotide position 217, causing the glutamic acid (E) at amino acid position 73 to be replaced by a lysine (K). 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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.00098	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.3	M;M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.9	.;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.71
MutPred		0.73		Gain of MoRF binding (P = 0.0369);Gain of MoRF binding (P = 0.0369);Gain of MoRF binding (P = 0.0369);
MVP		0.13
MPC		2.5
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.67
gMVP		0.97

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: rs2032658030; hg19: chr19-7747356;