rs267607137

Variant names:

• chr8-140360131-G-A
• rs267607137
• NM_001160372.4:c.1414C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-140360131-G-A
• chr8-140360131-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001160372.4(TRAPPC9):​c.1414C>T​(p.Arg472*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000378 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: TRAPPC9 NM_001160372.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.03

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-140360131-G-A is Pathogenic according to our data. Variant chr8-140360131-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-140360131-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC9	NM_001160372.4	c.1414C>T	p.Arg472*	stop_gained	Exon 9 of 23	ENST00000438773.4	NP_001153844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC9	ENST00000438773.4	c.1414C>T	p.Arg472*	stop_gained	Exon 9 of 23	1	NM_001160372.4	ENSP00000405060.3
TRAPPC9	ENST00000520857.5	c.943C>T	p.Arg315*	stop_gained	Exon 7 of 21	1		ENSP00000430116.1
TRAPPC9	ENST00000648948.2	c.1414C>T	p.Arg472*	stop_gained	Exon 9 of 23			ENSP00000498020.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251490 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727248

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.0000671 AC: 3 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000432 AC: 48 AN: 1112012

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74344

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241324 AN: 0.0000241324

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000441 AC: 0.0000440995 AN: 0.0000440995

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000374 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 13 Pathogenic:3

Jun 09, 2021

Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg472Ter variant in the TRAPPC9 gene has been already reported in the homozygous state in two separately consanguineous Tunisian families of three siblings with autosomal recessive microcephaly and intellectual disability (Philippe et al., 2009 and Mortreux et al.,2018). In vitro studies of the p.Arg472Ter variant revealed undetectable levels of TRAPPC9 protein in skin fibroblasts from a patient with the homozygous p.Arg472Ter variant (Philippe et al., 2009). The p.Arg472Ter is a very rare variant, reported in heterozygous state in the gnomAD (exome) database with AF=0.0032 % ( 8 alleles of 251,490). We interpret the p.Arg472Ter as a pathogenic variant.(ACMG criteria : PVS1,PP5,PM2,PP3) -

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 04, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1708C>T (p.R570*) alteration, located in exon 9 (coding exon 9) of the TRAPPC9 gene, consists of a C to T substitution at nucleotide position 1708. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 570. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been identified as homozygous in three brothers from a consanguineous Tunisian family with autosomal recessive intellectual disability, mild microcephaly, and white matter abnormalities (Philippe, 2009). Expression studies showed an undetectable level of TRAPPC9 protein in patient skin fibroblasts (Philippe, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Nov 08, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22549410, 30272317, 20004764, 29187737, 30853973, 30152084, 29031008, 32434006, 34737153) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.59
ClinPred		0.98	D
GERP RS		4.4
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs267607137; hg19: chr8-141370230;