rs746032983

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1 BS1 BS2

The NM_001128835.3(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 NM_001128835.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:2
• Conservation: PhyloP100: 0.316
• Publications: 1 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):

• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 0 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 27 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128835.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC2	NM_001011658.4	MANE Select	c.-97G>A		5_prime_UTR	Exon 2 of 6	NP_001011658.1	P0DI81-1
	TRAPPC2	NM_001128835.3		c.12G>A	p.Trp4*	stop_gained	Exon 2 of 6	NP_001122307.2	P0DI81-3
	TRAPPC2	NM_014563.6		c.-20+404G>A		intron	N/A	NP_055378.1	P0DI81-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAPPC2	ENST00000683983.1		c.12G>A	p.Trp4*	stop_gained	Exon 2 of 6	ENSP00000507474.1	P0DI81-3
	TRAPPC2	ENST00000380579.6	TSL:1 MANE Select	c.-97G>A		5_prime_UTR	Exon 2 of 6	ENSP00000369953.1	P0DI81-1
	TRAPPC2	ENST00000359680.9	TSL:1	c.-20+404G>A		intron	N/A	ENSP00000352708.5	P0DI81-1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 36 AN: 111900 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000394 AC: 37 AN: 93930 AF XY: 0.000336

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 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

African (AFR) AF: 0.0000805 AC: 1 AN: 12425

American (AMR) AF: 0.00 AC: 0 AN: 26775

Ashkenazi Jewish (ASJ) AF: 0.000688 AC: 10 AN: 14536

East Asian (EAS) AF: 0.00 AC: 0 AN: 24035

South Asian (SAS) AF: 0.00 AC: 0 AN: 37337

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25607

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2970

European-Non Finnish (NFE) AF: 0.000731 AC: 170 AN: 232483

Other (OTH) AF: 0.000608 AC: 14 AN: 23026

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

African (AFR) AF: 0.000261 AC: 8 AN: 30699

American (AMR) AF: 0.00 AC: 0 AN: 10594

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000470 AC: 25 AN: 53181

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.000692 Hom.: 11

Bravo AF: 0.000321

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 3

ExAC AF: 0.000125 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	1	Spondyloepiphyseal dysplasia tarda (3)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.32
Vest4		0.28
GERP RS		-0.14
PromoterAI		-0.013	Neutral
Mutation Taster		=174/26	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

Other links and lift over

dbSNP: rs746032983; hg19: chrX-13752240;