8-140252770-C-T

Position:

• chr8-140252770-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001160372.4(TRAPPC9):​c.2431+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,612,806 control chromosomes in the GnomAD database, including 13,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1083 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12511 hom.)
• Consequence: TRAPPC9 NM_001160372.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002083
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.21

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-140252770-C-T is Benign according to our data. Variant chr8-140252770-C-T is described in ClinVar as [Benign]. Clinvar id is 130626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.2431+7G>A		splice_region_variant, intron_variant		ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.2431+7G>A		splice_region_variant, intron_variant		1	NM_001160372.4	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16023 AN: 151904 Hom.: 1077 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0701

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.127 AC: 31828 AN: 249920 Hom.: 2578 AF XY: 0.123 AC XY: 16623 AN XY: 135252

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.00218

Gnomad SAS exome AF: 0.0763

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.124 AC: 181300 AN: 1460784 Hom.: 12511 Cov.: 32 AF XY: 0.123 AC XY: 89080 AN XY: 726758

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.0775

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.106 AC: 16040 AN: 152022 Hom.: 1083 Cov.: 32 AF XY: 0.107 AC XY: 7979 AN XY: 74308

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.0699

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.0985

Alfa AF: 0.121 Hom.: 2059

Bravo AF: 0.102

Asia WGS AF: 0.0590 AC: 208 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.120

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Intellectual disability, autosomal recessive 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.25
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs11166964; hg19: chr8-141262869;