18-31846768-T-C

Variant names:

• chr18-31846768-T-C
• rs1021897339
• NM_014939.5:c.3785A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014939.5(TRAPPC8):​c.3785A>G​(p.His1262Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,868 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRAPPC8 NM_014939.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC8	NM_014939.5	c.3785A>G	p.His1262Arg	missense_variant	Exon 26 of 29	ENST00000283351.10	NP_055754.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC8	ENST00000283351.10	c.3785A>G	p.His1262Arg	missense_variant	Exon 26 of 29	1	NM_014939.5	ENSP00000283351.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726742

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3785A>G (p.H1262R) alteration is located in exon 26 (coding exon 26) of the TRAPPC8 gene. This alteration results from a A to G substitution at nucleotide position 3785, causing the histidine (H) at amino acid position 1262 to be replaced by an arginine (R). 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	0.69
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.054	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.57		Gain of MoRF binding (P = 0.0184);.;
MVP		0.39
MPC		0.64
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.83

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: rs1021897339; hg19: chr18-29426731;