rs3735803

Positions:

• chr8-140450963-G-A

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.411C>T​(p.Asn137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,834 control chromosomes in the GnomAD database, including 185,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16588 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169313 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.35

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 8-140450963-G-A is Benign according to our data. Variant chr8-140450963-G-A is described in ClinVar as [Benign]. Clinvar id is 130639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4	c.411C>T	p.Asn137=	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.411C>T	p.Asn137=	synonymous_variant	2/23	1	NM_001160372.4	ENSP00000405060	P1
TRAPPC9	ENST00000648948.2	c.411C>T	p.Asn137=	synonymous_variant	2/23			ENSP00000498020	P1
TRAPPC9	ENST00000520857.5			upstream_gene_variant		1		ENSP00000430116

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70237 AN: 151914 Hom.: 16571 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.465 AC: 116833 AN: 251244 Hom.: 27879 AF XY: 0.471 AC XY: 63969 AN XY: 135794

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.521

Gnomad SAS exome AF: 0.504

Gnomad FIN exome AF: 0.543

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.479 AC: 700531 AN: 1461804 Hom.: 169313 Cov.: 72 AF XY: 0.481 AC XY: 349572 AN XY: 727192

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.516

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.543

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.474

GnomAD4 genome AF: 0.462 AC: 70294 AN: 152030 Hom.: 16588 Cov.: 32 AF XY: 0.463 AC XY: 34397 AN XY: 74290

Gnomad4 AFR AF: 0.411

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.549

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.454

Alfa AF: 0.474 Hom.: 34240

Bravo AF: 0.444

Asia WGS AF: 0.499 AC: 1733 AN: 3478

EpiCase AF: 0.482

EpiControl AF: 0.476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
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	-	- -

not specified Benign:2

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

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	-0.55
CADD	Benign	11
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs3735803; hg19: chr8-141461062; COSMIC: COSV66905749; COSMIC: COSV66905749;