X-13746826-CAA-CA

Variant names:

• chrX-13746826-CA-C
• rs312262845
• NM_003611.3:c.710delA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003611.3(OFD1):​c.710delA​(p.Lys237SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,065,099 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: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000067 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OFD1 NM_003611.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.15

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-13746826-CA-C is Pathogenic according to our data. Variant chrX-13746826-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 41142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-13746826-CA-C is described in Lovd as [Pathogenic]. Variant chrX-13746826-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OFD1	NM_003611.3	c.710delA	p.Lys237SerfsTer6	frameshift_variant	Exon 8 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.710delA	p.Lys237SerfsTer6	frameshift_variant	Exon 8 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 106939 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 30647 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000667 AC: 71 AN: 1065099 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 342117

Gnomad4 AFR exome AF: 0.000356

Gnomad4 AMR exome AF: 0.000422

Gnomad4 ASJ exome AF: 0.0000534

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000525

Gnomad4 OTH exome AF: 0.0000224

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 106939 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 30647

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

OFD1-related disorder Pathogenic:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OFD1 c.710delA variant is predicted to result in a frameshift and premature protein termination (p.Lys237Serfs*6). This variant has been reported as having arisen de novo in at least two individuals with oral-facial-digital syndrome type 1 (Prattichizzo et al. 2008. PubMed ID: 18546297; Alby et al. 2018. PubMed ID: 29193896). This variant is reported in 0.068% of alleles in individuals of Latino descent in gnomAD; however, the quality of data at this position is questionable and should be interpreted with caution. Frameshift variants in OFD1 are expected to be pathogenic. This variant is classified as pathogenic. -

COACH syndrome Pathogenic:1

-

Credence Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Orofaciodigital syndrome I Pathogenic:1

Dec 21, 2023

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). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are X-linked recessive; however, orofaciodigital syndrome I (MIM#311200) is X-linked dominant. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variants have been associated with several OFD1-related conditions and are known to have intrafamilial and interfamilial variability (PMID: 31373179; 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) 0302 - Variant is present in gnomAD (v2) <0.001; however, the data quality of this variant is poor in gnomAD and is likely to be an artefact. (I) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in ClinVar as pathogenic, and reported as de novo in at least two individuals with OFDI syndrome (PMID: 29193896, PMID: 18546297). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Jul 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41142). This sequence change creates a premature translational stop signal (p.Lys237Serfs*6) in the OFD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OFD1 are known to be pathogenic (PMID: 16783569, 18546297, 27081566). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with oral-facial-digital syndrome type I (PMID: 18546297). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -46

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

Publications

LitVar

Other links and lift over

dbSNP: rs312262845; hg19: chrX-13764945;