rs145503551

chr8-139731152-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001160372.4(TRAPPC9):c.3356G>A(p.Arg1119Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,613,984 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: TRAPPC9 NM_001160372.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.89

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007153362).
• BP6: Variant 8-139731152-C-T is Benign according to our data. Variant chr8-139731152-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437021.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000348 (53/152330) while in subpopulation EAS AF= 0.00465 (24/5160). AF 95% confidence interval is 0.00321. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC9	NM_001160372.4	c.3356G>A	p.Arg1119Gln	missense_variant	23/23	ENST00000438773.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.3356G>A	p.Arg1119Gln	missense_variant	23/23	1	NM_001160372.4	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00464

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000511 AC: 128 AN: 250514 Hom.: 0 AF XY: 0.000413 AC XY: 56 AN XY: 135692

Gnomad AFR exome AF: 0.000866

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00566

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461654 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727130

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00368

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74482

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00465

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000373 Hom.: 0

Bravo AF: 0.000616

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2016

- -

Intellectual disability, autosomal recessive 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

TRAPPC9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2019

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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Benign	0.57
DEOGEN2	Benign	0.019	T;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.52	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
Polyphen		0.15	B;B;P;B
Vest4		0.21, 0.28
MVP		0.19
MPC		0.10
ClinPred		0.0072	T
GERP RS		2.8
Varity_R		0.034
gMVP		0.35

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: rs145503551; hg19: chr8-140743395;