ENST00000683983.1:c.12G>A

Variant names:

• chrX-13734121-C-T
• rs746032983
• ENST00000683983.1:c.12G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BS1_Supporting BS2

The ENST00000683983.1(TRAPPC2):​c.12G>A​(p.Trp4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 511,094 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 83 hemizygotes in GnomAD. 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 0.00032 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00049 (0 hom. 73 hem.)
• Consequence: TRAPPC2 ENST00000683983.1 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:2
• Conservation: PhyloP100: 0.316

Genes affected

TRAPPC2 (HGNC:23068): (trafficking protein particle complex subunit 2) The protein encoded by this gene is thought to be part of a large multi-subunit complex involved in the targeting and fusion of endoplasmic reticulum-to-Golgi transport vesicles with their acceptor compartment. In addition, the encoded protein can bind c-myc promoter-binding protein 1 and block its transcriptional repression capability. Mutations in this gene are a cause of spondyloepiphyseal dysplasia tarda (SEDT). A processed pseudogene of this gene is located on chromosome 19, and other pseudogenes are found on chromosomes 8 and Y. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2010]

OFD1 (HGNC:2567): (OFD1 centriole and centriolar satellite protein) This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000322 (36/111900) while in subpopulation NFE AF= 0.00047 (25/53181). AF 95% confidence interval is 0.000326. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC2	NM_001011658.4	c.-97G>A		5_prime_UTR_variant	Exon 2 of 6	ENST00000380579.6	NP_001011658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC2	ENST00000683983.1	c.12G>A	p.Trp4*	stop_gained	Exon 2 of 6			ENSP00000507474.1
TRAPPC2	ENST00000380579.6	c.-97G>A		5_prime_UTR_variant	Exon 2 of 6	1	NM_001011658.4	ENSP00000369953.1
TRAPPC2	ENST00000359680.9	c.-20+404G>A		intron_variant	Intron 1 of 4	1		ENSP00000352708.5
TRAPPC2	ENST00000458511.7	c.-90+404G>A		intron_variant	Intron 1 of 5	5		ENSP00000392495.3
TRAPPC2	ENST00000519885.5	c.-20+404G>A		intron_variant	Intron 1 of 3	3		ENSP00000430725.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 36 AN: 111900 Hom.: 0 Cov.: 23 AF XY: 0.000293 AC XY: 10 AN XY: 34084

Gnomad AFR AF: 0.000261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000394 AC: 37 AN: 93930 Hom.: 0 AF XY: 0.000336 AC XY: 11 AN XY: 32784

Gnomad AFR exome AF: 0.000398

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000678

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000809

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000488 AC: 195 AN: 399194 Hom.: 0 Cov.: 0 AF XY: 0.000497 AC XY: 73 AN XY: 146744

Gnomad4 AFR exome AF: 0.0000805

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000688

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000731

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.000322 AC: 36 AN: 111900 Hom.: 0 Cov.: 23 AF XY: 0.000293 AC XY: 10 AN XY: 34084

Gnomad4 AFR AF: 0.000261

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000711 Hom.: 4

Bravo AF: 0.000321

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 3

ExAC AF: 0.000125 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondyloepiphyseal dysplasia tarda Pathogenic:2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

- -

Sep 08, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRAPPC2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	7.0
DANN	Benign	0.97
FATHMM_MKL	Benign	0.0088	N
Vest4		0.28
GERP RS		-0.14

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: rs746032983; hg19: chrX-13752240;