18-31849630-T-C

Variant names:

• chr18-31849630-T-C
• rs753777096
• NM_014939.5:c.3671A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014939.5(TRAPPC8):​c.3671A>G​(p.Glu1224Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRAPPC8 NM_014939.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

Genes affected

TRAPPC8 (HGNC:29169): (trafficking protein particle complex subunit 8) Involved in Golgi organization. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15452275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC8	NM_014939.5	c.3671A>G	p.Glu1224Gly	missense_variant	Exon 25 of 29	ENST00000283351.10	NP_055754.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC8	ENST00000283351.10	c.3671A>G	p.Glu1224Gly	missense_variant	Exon 25 of 29	1	NM_014939.5	ENSP00000283351.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461046 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726820

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3671A>G (p.E1224G) alteration is located in exon 25 (coding exon 25) of the TRAPPC8 gene. This alteration results from a A to G substitution at nucleotide position 3671, causing the glutamic acid (E) at amino acid position 1224 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0070	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.052
Sift	Benign	0.24	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.34		Gain of loop (P = 0.0166);.;
MVP		0.082
MPC		0.14
ClinPred		0.20	T
GERP RS		5.9
Varity_R		0.096
gMVP		0.27

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: rs753777096; hg19: chr18-29429593;