rs1555900734

Variant names:

• chrX-13736586-T-TTAAAAGAGCTGC
• rs1555900734
• NM_003611.3:c.220_221insTAAAAGAGCTGC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP5_Moderate

The NM_003611.3(OFD1):​c.220_221insTAAAAGAGCTGC​(p.Ser74delinsLeuLysGluLeuPro) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OFD1 NM_003611.3 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.71
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003611.3
• PM4: Nonframeshift variant in NON repetitive region in NM_003611.3.
• PP5: Variant X-13736586-T-TTAAAAGAGCTGC is Pathogenic according to our data. Variant chrX-13736586-T-TTAAAAGAGCTGC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559929.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003611.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.220_221insTAAAAGAGCTGC	p.Ser74delinsLeuLysGluLeuPro	disruptive_inframe_insertion	Exon 3 of 23	NP_003602.1
	OFD1	NM_001440947.1		c.220_221insTAAAAGAGCTGC	p.Ser74delinsLeuLysGluLeuPro	disruptive_inframe_insertion	Exon 3 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.220_221insTAAAAGAGCTGC	p.Ser74delinsLeuLysGluLeuPro	disruptive_inframe_insertion	Exon 3 of 22	NP_001317138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.220_221insTAAAAGAGCTGC	p.Ser74delinsLeuLysGluLeuPro	disruptive_inframe_insertion	Exon 3 of 23	ENSP00000344314.6
	OFD1	ENST00000380550.6	TSL:1	c.220_221insTAAAAGAGCTGC	p.Ser74delinsLeuLysGluLeuPro	disruptive_inframe_insertion	Exon 3 of 22	ENSP00000369923.3
	OFD1	ENST00000380567.6	TSL:5	n.220_221insTAAAAGAGCTGC		non_coding_transcript_exon	Exon 3 of 24	ENSP00000369941.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Orofaciodigital syndrome I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555900734; hg19: chrX-13754705;