X-13767252-C-T

Variant names:

• chrX-13767252-C-T
• rs1060500123
• NM_003611.3:c.2725C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003611.3(OFD1):​c.2725C>T​(p.Arg909*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R909R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OFD1 NM_003611.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.886
• Publications: 1 publications found

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]

OFD1 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome I

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 23

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Simpson-Golabi-Behmel syndrome type 2

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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-13767252-C-T is Pathogenic according to our data. Variant chrX-13767252-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 404165.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.2725C>T	p.Arg909*	stop_gained	Exon 20 of 23	ENST00000340096.11	NP_003602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OFD1	ENST00000340096.11	c.2725C>T	p.Arg909*	stop_gained	Exon 20 of 23	1	NM_003611.3	ENSP00000344314.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097356 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362724

African (AFR) AF: 0.0000379 AC: 1 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841326

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

OFD1-related disorder Pathogenic:1

May 19, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS2, PM2 -

Joubert syndrome;C1510460:Orofaciodigital syndrome I Pathogenic:1

Mar 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg909*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OFD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 404165). For these reasons, this variant has been classified as Pathogenic. -

Orofaciodigital syndrome I Pathogenic:1

Nov 29, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD,PM2_SUP -

Primary ciliary dyskinesia Pathogenic:1

Dec 11, 2023

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature termination codon (p.Arg909*) in the OFD1 gene and is expected to result in an absent or disrupted protein product. The c.2725C>T variant is absent in population databases (no allele frequency in gnomAD) and has not been previously reported in the literature. ClinVar contains an entry for this variant (variation ID 404165): it was reported twice in patients with OFD1-related disorders and classified as Pathogenic. The proband and his affected uncle both possessed the c.2725C>T in a hemizygous state, while the clinically healthy mother was a heterozygous carrier. For these reasons, this variant has been classified as Pathogenic. -

Respiratory ciliopathies including non-CF bronchiectasis Pathogenic:1

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.55	D
PhyloP100		0.89
Vest4		0.66
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1060500123; hg19: chrX-13785371; COSMIC: COSV57424540; COSMIC: COSV57424540;