rs112551069

chr8-139732009-G-Achr8-139732009-G-Cchr8-139732009-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001160372.4(TRAPPC9):c.3249C>T(p.Phe1083=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,596,098 control chromosomes in the GnomAD database, including 64 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 0.0050 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (61 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.51

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-139732009-G-A is Benign according to our data. Variant chr8-139732009-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130632.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.005 (762/152352) while in subpopulation NFE AF= 0.00747 (508/68032). AF 95% confidence interval is 0.00693. There are 3 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.3249C>T	p.Phe1083=	synonymous_variant	22/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.3249C>T	p.Phe1083=	synonymous_variant	22/23	1	NM_001160372.4	P1

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152234 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00617 AC: 1351 AN: 218814 Hom.: 8 AF XY: 0.00642 AC XY: 757 AN XY: 117972

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00480

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00586

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.00814

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.00810 AC: 11701 AN: 1443746 Hom.: 61 Cov.: 32 AF XY: 0.00801 AC XY: 5738 AN XY: 716254

Gnomad4 AFR exome AF: 0.00115

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00610

Gnomad4 FIN exome AF: 0.00899

Gnomad4 NFE exome AF: 0.00895

Gnomad4 OTH exome AF: 0.00794

GnomAD4 genome AF: 0.00500 AC: 762 AN: 152352 Hom.: 3 Cov.: 33 AF XY: 0.00460 AC XY: 343 AN XY: 74496

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.00747

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00544 Hom.: 0

Bravo AF: 0.00492

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TRAPPC9: BP4, BP7, BS2 -

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 17, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

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	-0.48
Cadd	Benign	9.2
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112551069; hg19: chr8-140744252;