rs312262868

Positions:

• chrX-13755207-CTCAA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003611.3(OFD1):​c.1193_1196del​(p.Gln398LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,086,337 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: OFD1 NM_003611.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-13755207-CTCAA-C is Pathogenic according to our data. Variant chrX-13755207-CTCAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 41065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13755207-CTCAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OFD1	NM_003611.3	c.1193_1196del	p.Gln398LeufsTer2	frameshift_variant	12/23	ENST00000340096.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OFD1	ENST00000340096.11	c.1193_1196del	p.Gln398LeufsTer2	frameshift_variant	12/23	1	NM_003611.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1086337 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 352175

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	OFD1: PVS1, PS2, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2017	The c.1193_1196delAATC pathogenic variant in the OFD1 gene has been reported previously in association with Oral-Facial-Digital syndrome type 1 (OFD1), including a de novo occurrence (Shimojima et al., 2013; Prattichizzo et al., 2008). The deletion causes a frameshift starting with codon Glutamine 398, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Gln398LeufsX2. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, the variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Orofaciodigital syndrome I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 22, 2023	Criteria applied: PVS1,PS4_MOD,PM2_SUP -

Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs312262868; hg19: chrX-13773326;