chrX-13734776-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003611.3(OFD1):​c.-296G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,056,115 control chromosomes in the GnomAD database, including 26,388 homozygotes. There are 86,786 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (3264 hom., 9650 hem., cov: 24)
  • Exomes 𝑓: 0.26 (23124 hom. 77136 hem.)
• Consequence: OFD1 NM_003611.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-13734776-G-T is Benign according to our data. Variant chrX-13734776-G-T is described in ClinVar as Benign. ClinVar VariationId is 41157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

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>T		5_prime_UTR	Exon 1 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.-296G>T		5_prime_UTR	Exon 1 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.-296G>T		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>T		5_prime_UTR	Exon 1 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000922711.1		c.-296G>T		5_prime_UTR	Exon 1 of 23	ENSP00000592770.1
	OFD1	ENST00000922712.1		c.-296G>T		5_prime_UTR	Exon 1 of 22	ENSP00000592771.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 31241 AN: 111742 Hom.: 3257 Cov.: 24

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.260 AC: 245282 AN: 944320 Hom.: 23124 Cov.: 30 AF XY: 0.265 AC XY: 77136 AN XY: 290982

African (AFR) AF: 0.258 AC: 5597 AN: 21661

American (AMR) AF: 0.540 AC: 7125 AN: 13194

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 3251 AN: 13468

East Asian (EAS) AF: 0.441 AC: 11085 AN: 25133

South Asian (SAS) AF: 0.468 AC: 16048 AN: 34327

European-Finnish (FIN) AF: 0.244 AC: 5241 AN: 21453

Middle Eastern (MID) AF: 0.272 AC: 666 AN: 2445

European-Non Finnish (NFE) AF: 0.240 AC: 185323 AN: 772824

Other (OTH) AF: 0.275 AC: 10946 AN: 39815

GnomAD4 genome AF: 0.280 AC: 31267 AN: 111795 Hom.: 3264 Cov.: 24 AF XY: 0.284 AC XY: 9650 AN XY: 34005

African (AFR) AF: 0.260 AC: 8011 AN: 30835

American (AMR) AF: 0.462 AC: 4908 AN: 10620

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 648 AN: 2642

East Asian (EAS) AF: 0.440 AC: 1539 AN: 3494

South Asian (SAS) AF: 0.467 AC: 1277 AN: 2735

European-Finnish (FIN) AF: 0.232 AC: 1404 AN: 6041

Middle Eastern (MID) AF: 0.272 AC: 58 AN: 213

European-Non Finnish (NFE) AF: 0.242 AC: 12839 AN: 53015

Other (OTH) AF: 0.297 AC: 452 AN: 1522

Alfa AF: 0.253 Hom.: 18735

Bravo AF: 0.302

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.10
DANN	Benign	0.59
PhyloP100		-1.8
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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;