rs587776752

Variant names:

• chrX-13719866-C-T
• rs587776752
• NM_001011658.4:c.93+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 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 region, 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_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.74
• Publications: 5 publications found

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]

OFD1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 23

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Simpson-Golabi-Behmel syndrome type 2

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 11512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAPPC2	NM_001011658.4	c.93+5G>A		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000380579.6	NP_001011658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAPPC2	ENST00000380579.6	c.93+5G>A		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_001011658.4	ENSP00000369953.1
TRAPPC2	ENST00000683983.1	c.195+5G>A		splice_region_variant, intron_variant	Intron 3 of 5			ENSP00000507474.1
TRAPPC2	ENST00000359680.9	c.93+5G>A		splice_region_variant, intron_variant	Intron 2 of 4	1		ENSP00000352708.5
TRAPPC2	ENST00000458511.7	c.93+5G>A		splice_region_variant, intron_variant	Intron 3 of 5	5		ENSP00000392495.3
TRAPPC2	ENST00000518847.2	c.93+5G>A		splice_region_variant, intron_variant	Intron 2 of 4	4		ENSP00000428900.2
TRAPPC2	ENST00000519885.5	c.93+5G>A		splice_region_variant, intron_variant	Intron 2 of 3	3		ENSP00000430725.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 147293 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 11512). 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. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondyloepiphyseal dysplasia tarda, X-linked Pathogenic:1

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 09, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.87
PhyloP100		2.7
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776752; hg19: chrX-13737985;