8-139988739-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001160372.4(TRAPPC9):c.2797G>A(p.Gly933Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,550,178 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G933G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (61 hom.)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.77

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004834801).
• BP6: Variant 8-139988739-C-T is Benign according to our data. Variant chr8-139988739-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130629.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00675 (1028/152226) while in subpopulation SAS AF= 0.0245 (118/4814). AF 95% confidence interval is 0.0209. There are 5 homozygotes in gnomad4. There are 509 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.2797G>A	p.Gly933Ser	missense_variant	19/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.2797G>A	p.Gly933Ser	missense_variant	19/23	1	NM_001160372.4	P1

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152108 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00574 AC: 895 AN: 155810 Hom.: 22 AF XY: 0.00689 AC XY: 566 AN XY: 82170

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000886

Gnomad SAS exome AF: 0.0253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000796

Gnomad OTH exome AF: 0.00386

GnomAD4 exome AF: 0.00274 AC: 3825 AN: 1397952 Hom.: 61 Cov.: 34 AF XY: 0.00346 AC XY: 2386 AN XY: 689596

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0256

Gnomad4 FIN exome AF: 0.0000410

Gnomad4 NFE exome AF: 0.000541

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00675 AC: 1028 AN: 152226 Hom.: 5 Cov.: 33 AF XY: 0.00684 AC XY: 509 AN XY: 74422

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00204 Hom.: 5

Bravo AF: 0.00663

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0139 AC: 54

ESP6500EA AF: 0.000685 AC: 5

ExAC AF: 0.00690 AC: 305

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.70	D
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N;N;.;N
MutationTaster	Benign	0.75	N;N;N
PrimateAI	Benign	0.33	T
Polyphen		0.0050	B;B;B;B
Vest4		0.29, 0.30
MVP		0.36
MPC		0.085
ClinPred		0.015	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.12

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: rs114949291; hg19: chr8-140998947; COSMIC: COSV66905768; COSMIC: COSV66905768;