rs148805943

chr8-139885922-G-Achr8-139885922-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001160372.4(TRAPPC9):c.3012C>T(p.Asn1004=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,574,250 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.03

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-139885922-G-A is Benign according to our data. Variant chr8-139885922-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00155 (236/152326) while in subpopulation NFE AF= 0.00221 (150/68020). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.3012C>T	p.Asn1004=	synonymous_variant	21/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.3012C>T	p.Asn1004=	synonymous_variant	21/23	1	NM_001160372.4	P1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00180 AC: 339 AN: 188720 Hom.: 0 AF XY: 0.00185 AC XY: 186 AN XY: 100784

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00156

Gnomad FIN exome AF: 0.0000600

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00223 AC: 3171 AN: 1421924 Hom.: 7 Cov.: 32 AF XY: 0.00226 AC XY: 1591 AN XY: 703382

Gnomad4 AFR exome AF: 0.000427

Gnomad4 AMR exome AF: 0.00216

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.0000599

Gnomad4 NFE exome AF: 0.00246

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74488

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	TRAPPC9: BP4 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2016

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2021

This variant is classified as likely 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	-0.36
CADD	Benign	8.1
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148805943; hg19: chr8-140898166;