NM_003611.3:c.-315G>A

Variant names:

• chrX-13734757-G-A
• rs188480668
• NM_003611.3:c.-315G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003611.3(OFD1):​c.-315G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000107 in 931,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom. 1 hem.)
• Consequence: OFD1 NM_003611.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.337
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).

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.-315G>A		5_prime_UTR	Exon 1 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.-315G>A		5_prime_UTR	Exon 1 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.-315G>A		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.-315G>A		5_prime_UTR	Exon 1 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000922711.1		c.-315G>A		5_prime_UTR	Exon 1 of 23	ENSP00000592770.1
	OFD1	ENST00000922712.1		c.-315G>A		5_prime_UTR	Exon 1 of 22	ENSP00000592771.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 931662 Hom.: 0 Cov.: 28 AF XY: 0.00000354 AC XY: 1 AN XY: 282812

African (AFR) AF: 0.00 AC: 0 AN: 21458

American (AMR) AF: 0.00 AC: 0 AN: 12200

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 2375

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 765602

Other (OTH) AF: 0.00 AC: 0 AN: 39127

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.7
DANN	Benign	0.78
PhyloP100		0.34
PromoterAI		0.0093	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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;