chrX-13734776-G-C

Variant names:

• chrX-13734776-G-C
• rs2285635
• NM_003611.3:c.-296G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003611.3(OFD1):​c.-296G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,056,350 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000040 (0 hom. 19 hem.)
• Consequence: OFD1 NM_003611.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• Publications: 9 publications found

Genes affected

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]

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]

TRAPPC2 Gene-Disease associations (from GenCC):

• spondyloepiphyseal dysplasia tarda, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• spondyloepiphyseal dysplasia tarda

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000402 (38/944568) while in subpopulation SAS AF = 0.00111 (38/34341). AF 95% confidence interval is 0.000828. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 19 XL,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003611.3. 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
	OFD1	NM_003611.3	MANE Select	c.-296G>C		5_prime_UTR	Exon 1 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.-296G>C		5_prime_UTR	Exon 1 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.-296G>C		5_prime_UTR	Exon 1 of 22	NP_001317138.1	O75665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.-296G>C		5_prime_UTR	Exon 1 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000922711.1		c.-296G>C		5_prime_UTR	Exon 1 of 23	ENSP00000592770.1
	OFD1	ENST00000922712.1		c.-296G>C		5_prime_UTR	Exon 1 of 22	ENSP00000592771.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111782 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000402 AC: 38 AN: 944568 Hom.: 0 Cov.: 30 AF XY: 0.0000653 AC XY: 19 AN XY: 291008

African (AFR) AF: 0.00 AC: 0 AN: 21663

American (AMR) AF: 0.00 AC: 0 AN: 13208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13472

East Asian (EAS) AF: 0.00 AC: 0 AN: 25149

South Asian (SAS) AF: 0.00111 AC: 38 AN: 34341

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2445

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 772988

Other (OTH) AF: 0.00 AC: 0 AN: 39827

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111782 Hom.: 0 Cov.: 24 AF XY: 0.0000294 AC XY: 1 AN XY: 33960

African (AFR) AF: 0.00 AC: 0 AN: 30781

American (AMR) AF: 0.00 AC: 0 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.000364 AC: 1 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6045

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53033

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 18735

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.11
DANN	Benign	0.54
PhyloP100		-1.8
PromoterAI		-0.017	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2285635; hg19: chrX-13752895;