chrX-13760436-ACT-A

Variant names:

• chrX-13760436-ACT-A
• rs312262887
• NM_003611.3:c.1979_1980delCT

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.1979_1980delCT​(p.Ser660CysfsTer40) 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: 22)
• Consequence: OFD1 NM_003611.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0840

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-13760436-ACT-A is Pathogenic according to our data. Variant chrX-13760436-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 41089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.1979_1980delCT	p.Ser660CysfsTer40	frameshift_variant	Exon 16 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.1979_1980delCT	p.Ser660CysfsTer40	frameshift_variant	Exon 16 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 22

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

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orofaciodigital syndrome I Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with orofaciodigital syndrome I (MIM#311200), and other OFD1-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant X-linked disease. Variants reported to cause Joubert syndrome 10 (MIM#300804), Simpson-Golabi-Behmel syndrome, type 2 (MIM#300209) and retinitis pigmentosa 23 (MIM#300424) have been observed in asymptomatic female carriers. Variants causing OFD1 (MIM#311200) have been reported almost exclusively in females, where male lethality is suspected (PMID: 31373179, PMID: 23033313, PMID: 16783569, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity, where intra- and interfamilial phenotypic variability has been reported (PMID: 23033313). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in female patients with orofaciodigital syndrome I (OFD1) (Decipher, PMID: 18546297). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (ClinVar), and observed in two de novo patients, and a family with OFD1 (PMID: 18546297, PMID: 23033313). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Mar 07, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1979_1980delCT variant in the OFD1 gene has been reported previously as a likely de novo variant in two unrelated individuals with a clinical diagnosis of Oral-Facial-Digital syndrome type 1 (Prattichizzo et al., 2008). The c.1979_1980delCT variant causes a frameshift starting with codon Serine 660, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Ser660CysfsX40. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1979_1980delCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1979_1980delCT as a pathogenic variant, -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs312262887; hg19: chrX-13778555;