rs797044945

Positions:

• chrX-13768079-TTAAAA-T

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.2789_2793del​(p.Ile930LysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: OFD1 NM_003611.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.240

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-13768079-TTAAAA-T is Pathogenic according to our data. Variant chrX-13768079-TTAAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 208769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OFD1	NM_003611.3	c.2789_2793del	p.Ile930LysfsTer8	frameshift_variant	21/23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.2789_2793del	p.Ile930LysfsTer8	frameshift_variant	21/23	1	NM_003611.3	ENSP00000344314	P1

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 2016	The c.2789_2793delTAAAA pathogenic mutation, located in coding exon 21 of the OFD1 gene, results from a deletion of 5 nucleotides at nucleotide positions 2789 to 2793, causing a translational frameshift with a predicted alternate stop codon (p.I930Kfs*8). This mutation was first reported in an individual with clinical features consistent with Joubert syndrome, including macrocephaly, postaxial polydactyly, intellectual disability, molar tooth sign on brain MRI, chronic sinusitis and bronchitis, juvenile retinopathy, and obesity (Thauvin-Robinet C et al. Clin. Genet., 2013 Jul;84:86-90). In addition, this mutation was confirmed to occur de novo by our laboratory in an individual with dysmorphic features, postaxial polydactyly, intellectual disability, and obesity (Farwell KD et al. Genet. Med., 2015 Jul;17:578-86). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2013

- -

Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in OFD1 are known to be pathogenic (PMID: 16783569, 18546297, 27081566). This variant has been reported as hemizygous in the literature in individuals affected with Joubert syndrome, and determined to be de novo in at lease one of them (PMID: 23036093, 25356970). ClinVar contains an entry for this variant (Variation ID: 208769). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile930Lysfs*8) in the OFD1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044945; hg19: chrX-13786198;