rs145782440

chr8-140371138-C-T

Variant summary

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

The NM_001160372.4(TRAPPC9):c.1177G>A(p.Glu393Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.52

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.1177G>A	p.Glu393Lys	missense_variant	8/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1177G>A	p.Glu393Lys	missense_variant	8/23	1	NM_001160372.4	P1
TRAPPC9	ENST00000520857.5	c.709G>A	p.Glu237Lys	missense_variant	6/21	1
TRAPPC9	ENST00000648948.2	c.1177G>A	p.Glu393Lys	missense_variant	8/23			P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000801 AC: 20 AN: 249768 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135162

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000579

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: 0.000125

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.0000825 AC XY: 60 AN XY: 727168

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74502

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 22, 2015

- -

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2021

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. 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: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 212415). This variant has not been reported in the literature in individuals affected with TRAPPC9-related conditions. This variant is present in population databases (rs145782440, gnomAD 0.01%). This sequence change replaces glutamic acid with lysine at codon 491 of the TRAPPC9 protein (p.Glu491Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.058	T;T;.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M;M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
Polyphen		0.99	D;D;D;D
Vest4		0.90, 0.92
MVP		0.22
MPC		1.5
ClinPred		0.39	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.80

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: rs145782440; hg19: chr8-141381237; COSMIC: COSV66899432;