rs148523016

Positions:

• chr8-140458405-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031466.8(TRAPPC9):​c.-135A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,590,156 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: TRAPPC9 NM_031466.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0150

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031356514).
• BP6: Variant 8-140458405-T-C is Benign according to our data. Variant chr8-140458405-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000544 (81/148840) while in subpopulation EAS AF= 0.0146 (75/5152). AF 95% confidence interval is 0.0119. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAPPC9	XM_011517326.3	c.160A>G	p.Ser54Gly	missense_variant	1/22		XP_011515628.1
TRAPPC9	XM_011517328.3	c.160A>G	p.Ser54Gly	missense_variant	1/22		XP_011515630.1
TRAPPC9	XM_047422294.1	c.160A>G	p.Ser54Gly	missense_variant	1/21		XP_047278250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000648948.2	c.-135A>G		5_prime_UTR_variant	1/23			ENSP00000498020.1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 81 AN: 148746 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000489

GnomAD3 exomes AF: 0.00161 AC: 341 AN: 212190 Hom.: 1 AF XY: 0.00167 AC XY: 192 AN XY: 115232

Gnomad AFR exome AF: 0.000580

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0184

Gnomad SAS exome AF: 0.00100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000412 AC: 594 AN: 1441316 Hom.: 3 Cov.: 34 AF XY: 0.000428 AC XY: 306 AN XY: 715366

Gnomad4 AFR exome AF: 0.000161

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000725

Gnomad4 OTH exome AF: 0.000757

GnomAD4 genome AF: 0.000544 AC: 81 AN: 148840 Hom.: 0 Cov.: 31 AF XY: 0.000686 AC XY: 50 AN XY: 72844

Gnomad4 AFR AF: 0.0000261

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0146

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.000907

ExAC AF: 0.00156 AC: 188

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 12, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2017

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, Recessive Benign:1

Likely 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_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.2
DANN	Benign	0.41
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.0030
Sift	Benign	1.0	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.080
MVP		0.067
MPC		0.46
ClinPred		0.0013	T
GERP RS		-0.12
gMVP		0.10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148523016; hg19: chr8-141468504;