8-140458344-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The XM_011517326.3(TRAPPC9):c.221C>A(p.Ala74Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000643 in 1,586,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: TRAPPC9 XM_011517326.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.515

Genes affected

TRAPPC9 (HGNC:30832): (trafficking protein particle complex subunit 9) This gene encodes a protein that likely plays a role in NF-kappa-B signaling. Mutations in this gene have been associated with autosomal-recessive cognitive disability. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02950573).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000592 (85/1434856) while in subpopulation MID AF= 0.00175 (10/5728). AF 95% confidence interval is 0.000946. There are 1 homozygotes in gnomad4_exome. There are 52 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	XM_011517326.3	c.221C>A	p.Ala74Glu	missense_variant	1/22
TRAPPC9	XM_011517328.3	c.221C>A	p.Ala74Glu	missense_variant	1/22
TRAPPC9	XM_047422294.1	c.221C>A	p.Ala74Glu	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000648948.2	c.-74C>A		5_prime_UTR_variant	1/23			P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151642 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000112 AC: 23 AN: 205122 Hom.: 0 AF XY: 0.000118 AC XY: 13 AN XY: 110234

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000342

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.0000592 AC: 85 AN: 1434856 Hom.: 1 Cov.: 34 AF XY: 0.0000731 AC XY: 52 AN XY: 711046

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000500

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: 0.0000609

Gnomad4 OTH exome AF: 0.0000842

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151756 Hom.: 0 Cov.: 31 AF XY: 0.0000809 AC XY: 6 AN XY: 74172

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000744 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2021

The c.221C>A (p.A74E) alteration is located in exon 1 (coding exon 1) of the TRAPPC9 gene. This alteration results from a C to A substitution at nucleotide position 221, causing the alanine (A) at amino acid position 74 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, autosomal recessive 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 10, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 74 of the TRAPPC9 protein (p.Ala74Glu). This variant is present in population databases (rs139214686, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TRAPPC9-related conditions. ClinVar contains an entry for this variant (Variation ID: 547917). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	3.6
Dann	Benign	0.88
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.015
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.83	P
Vest4		0.11
MVP		0.048
MPC		0.64
ClinPred		0.14	T
GERP RS		-0.54
gMVP		0.057

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139214686; hg19: chr8-141468443;