NM_003611.3:c.-315G>C

Variant names:

• chrX-13734757-G-C
• rs188480668
• NM_003611.3:c.-315G>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.-315G>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 0.00125 in 1,044,304 control chromosomes in the GnomAD database, including 9 homozygotes. There are 331 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 0.0062 (6 hom., 197 hem., cov: 23)
  • Exomes 𝑓: 0.00064 (3 hom. 134 hem.)
• Consequence: OFD1 NM_003611.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.337
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.62).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00625 (704/112644) while in subpopulation AFR AF = 0.0216 (672/31062). AF 95% confidence interval is 0.0203. There are 6 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 XL,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.-315G>C		5_prime_UTR_variant	Exon 1 of 23	ENST00000340096.11	NP_003602.1
TRAPPC2	NM_001011658.4	c.-394C>G		upstream_gene_variant		ENST00000380579.6	NP_001011658.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.-315G>C		5_prime_UTR_variant	Exon 1 of 23	1	NM_003611.3	ENSP00000344314.6
TRAPPC2	ENST00000380579.6	c.-394C>G		upstream_gene_variant		1	NM_001011658.4	ENSP00000369953.1
TRAPPC2	ENST00000683983.1	c.-286C>G		upstream_gene_variant				ENSP00000507474.1
TRAPPC2	ENST00000359680.9	c.-252C>G		upstream_gene_variant		1		ENSP00000352708.5
TRAPPC2	ENST00000458511.7	c.-322C>G		upstream_gene_variant		5		ENSP00000392495.3
TRAPPC2	ENST00000519885.5	c.-252C>G		upstream_gene_variant		3		ENSP00000430725.1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 702 AN: 112593 Hom.: 6 Cov.: 23

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00592

GnomAD4 exome AF: 0.000643 AC: 599 AN: 931660 Hom.: 3 Cov.: 28 AF XY: 0.000474 AC XY: 134 AN XY: 282812

African (AFR) AF: 0.0237 AC: 508 AN: 21456

American (AMR) AF: 0.00107 AC: 13 AN: 12200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13176

East Asian (EAS) AF: 0.0000414 AC: 1 AN: 24168

South Asian (SAS) AF: 0.00 AC: 0 AN: 32802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20754

Middle Eastern (MID) AF: 0.000421 AC: 1 AN: 2375

European-Non Finnish (NFE) AF: 0.0000418 AC: 32 AN: 765602

Other (OTH) AF: 0.00112 AC: 44 AN: 39127

GnomAD4 genome AF: 0.00625 AC: 704 AN: 112644 Hom.: 6 Cov.: 23 AF XY: 0.00566 AC XY: 197 AN XY: 34796

African (AFR) AF: 0.0216 AC: 672 AN: 31062

American (AMR) AF: 0.00149 AC: 16 AN: 10741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2765

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53250

Other (OTH) AF: 0.00585 AC: 9 AN: 1539

Alfa AF: 0.00377 Hom.: 6

Bravo AF: 0.00655

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 04, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.0
DANN	Benign	0.62
PhyloP100		0.34
PromoterAI		-0.080	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)		0.0		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: rs188480668; hg19: chrX-13752876;