X-13755207-CTCAA-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003611.3(OFD1):c.1193_1196delAATC(p.Gln398fs) 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
NM_003611.3 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OFD1 | NM_003611.3 | c.1193_1196delAATC | p.Gln398fs | frameshift_variant | 12/23 | ENST00000340096.11 | NP_003602.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OFD1 | ENST00000340096.11 | c.1193_1196delAATC | p.Gln398fs | frameshift_variant | 12/23 | 1 | NM_003611.3 | ENSP00000344314.6 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
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23
GnomAD4 exome AF: 9.21e-7 AC: 1AN: 1086337Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 352175
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GnomAD4 genome Cov.: 23
GnomAD4 genome
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23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
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. - |
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,PS2_MOD - |
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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at