rs587776752

Positions:

• chrX-13719866-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001011658.4(TRAPPC2):​c.93+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TRAPPC2 NM_001011658.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.74

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:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-13719866-C-T is Pathogenic according to our data. Variant chrX-13719866-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13719866-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAPPC2	NM_001011658.4	c.93+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000380579.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAPPC2	ENST00000380579.6	c.93+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001011658.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 11512). This variant has been observed in individuals with spondyloepiphyseal dysplasia tarda (PMID: 11326333, 15221797, 22563562, 26252088). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the TRAPPC2 gene. It does not directly change the encoded amino acid sequence of the TRAPPC2 protein. It affects a nucleotide within the consensus splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

Spondyloepiphyseal dysplasia tarda, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant was co-segregated with Spondyloepiphyseal dysplasia tarda in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 11326333, 15221797) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 11326333, 15221797, PS4_S). The variant has been reported to be associated with TRAPPC2 related disorder (ClinVar ID: VCV000011512).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2021

The c.93+5G>A intronic alteration results from a G to A substitution 5 nucleotides after exon 3 (coding exon 1) of the TRAPPC2 gene. Based on data from the Genome Aggregation Database (gnomAD), the TRAPPC2 c.93+5G>A alteration was not observed, with coverage at this position. This alteration was reported by Tiller, et al. (2001) in an affected family with 21 affected males spread over five generations. The mutation cosegregated with the affected phenotype and in known carriers, with two exceptions. One was a phenotypically normal 10 year old boy, and the other was a man of normal stature who denied symptoms of osteoarthritis. An unrelated affected individual was also found to have this alteration (Tiller, 2001). The c.93+5G nucleotide is conserved through available reptile species. Tiller, et al. (2001) reported the functional effect of this alteration showed skipping of exon 3. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Spondyloepiphyseal dysplasia tarda Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776752; hg19: chrX-13737985;