rs34179337

Positions:

• chr8-140360087-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001160372.4(TRAPPC9):​c.1458C>T​(p.Phe486=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00177 in 1,614,176 control chromosomes in the GnomAD database, including 33 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 0.0078 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: TRAPPC9 NM_001160372.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.80

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-140360087-G-A is Benign according to our data. Variant chr8-140360087-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130621.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00781 (1190/152286) while in subpopulation AFR AF= 0.0254 (1054/41534). AF 95% confidence interval is 0.0241. There are 15 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.1458C>T	p.Phe486=	synonymous_variant	9/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1458C>T	p.Phe486=	synonymous_variant	9/23	1	NM_001160372.4	P1
TRAPPC9	ENST00000520857.5	c.990C>T	p.Phe330=	synonymous_variant	7/21	1
TRAPPC9	ENST00000648948.2	c.1458C>T	p.Phe486=	synonymous_variant	9/23			P1

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1189 AN: 152168 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00325 AC: 817 AN: 251496 Hom.: 8 AF XY: 0.00256 AC XY: 348 AN XY: 135922

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0172

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00114 AC: 1669 AN: 1461890 Hom.: 18 Cov.: 31 AF XY: 0.00102 AC XY: 745 AN XY: 727246

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00781 AC: 1190 AN: 152286 Hom.: 15 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74472

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0151

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00398 Hom.: 3

Bravo AF: 0.00969

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Intellectual Disability, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.8
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34179337; hg19: chr8-141370186;