8-140451086-A-G

Position:

• chr8-140451086-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001160372.4(TRAPPC9):​c.288T>C​(p.Phe96Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,678 control chromosomes in the GnomAD database, including 254,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23775 hom., cov: 31)
  • Exomes 𝑓: 0.56 (230820 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.774

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]

TRAPPC9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-140451086-A-G is Benign according to our data. Variant chr8-140451086-A-G is described in ClinVar as [Benign]. Clinvar id is 130635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-140451086-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.774 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4	c.288T>C	p.Phe96Phe	synonymous_variant	2/23	ENST00000438773.4	NP_001153844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.288T>C	p.Phe96Phe	synonymous_variant	2/23	1	NM_001160372.4	ENSP00000405060.3
TRAPPC9	ENST00000648948.2	c.288T>C	p.Phe96Phe	synonymous_variant	2/23			ENSP00000498020.1

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84602 AN: 151742 Hom.: 23753 Cov.: 31

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.540 AC: 135646 AN: 251372 Hom.: 37414 AF XY: 0.545 AC XY: 74024 AN XY: 135866

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.542

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.560 AC: 819183 AN: 1461818 Hom.: 230820 Cov.: 84 AF XY: 0.561 AC XY: 407877 AN XY: 727210

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.610

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.556

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.557 AC: 84662 AN: 151860 Hom.: 23775 Cov.: 31 AF XY: 0.556 AC XY: 41261 AN XY: 74190

Gnomad4 AFR AF: 0.549

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.605

Gnomad4 EAS AF: 0.532

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.558

Alfa AF: 0.571 Hom.: 9961

Bravo AF: 0.545

Asia WGS AF: 0.542 AC: 1880 AN: 3478

EpiCase AF: 0.566

EpiControl AF: 0.565

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

Intellectual disability, autosomal recessive 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Intellectual Disability, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.53
DANN	Benign	0.56

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: rs3735802; hg19: chr8-141461185;