rs117685875

Variant names:

• chr8-140287720-G-A
• rs117685875
• NM_001160372.4:c.1869C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001160372.4(TRAPPC9):​c.1869C>T​(p.Ser623Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,128 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (11 hom., cov: 32)
  • Exomes 𝑓: 0.014 (179 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.873

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-140287720-G-A is Benign according to our data. Variant chr8-140287720-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.873 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0096 (1461/152266) while in subpopulation NFE AF= 0.0159 (1082/68016). AF 95% confidence interval is 0.0151. There are 11 homozygotes in gnomad4. There are 674 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4	c.1869C>T	p.Ser623Ser	synonymous_variant	Exon 13 of 23	ENST00000438773.4	NP_001153844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1869C>T	p.Ser623Ser	synonymous_variant	Exon 13 of 23	1	NM_001160372.4	ENSP00000405060.3

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1462 AN: 152148 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00818

GnomAD3 exomes AF: 0.00841 AC: 2114 AN: 251304 Hom.: 19 AF XY: 0.00797 AC XY: 1083 AN XY: 135866

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00602

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.0138 AC: 20214 AN: 1461862 Hom.: 179 Cov.: 32 AF XY: 0.0133 AC XY: 9669 AN XY: 727230

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.00438

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00669

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00960 AC: 1461 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74452

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00987

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.00810

Alfa AF: 0.0124 Hom.: 12

Bravo AF: 0.0100

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0127

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual Disability, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 03, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

TRAPPC9-related disorder Benign:1

Jun 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.1
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs117685875; hg19: chr8-141297819;