rs312262830

Variant names:

• chrX-13739016-TAAAG-T
• rs312262830
• NM_003611.3:c.400_403delGAAA

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.400_403delGAAA​(p.Glu134IlefsTer10) variant causes a frameshift change. 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: 23)
• Consequence: OFD1 NM_003611.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.81
• Publications: 6 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):

• Joubert syndrome 10

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• OFD1-related ciliopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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-13739016-TAAAG-T is Pathogenic according to our data. Variant chrX-13739016-TAAAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	NM_003611.3	MANE Select	c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 23	NP_003602.1	O75665-1
	OFD1	NM_001440947.1		c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 22	NP_001427876.1
	OFD1	NM_001330209.2		c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 22	NP_001317138.1	O75665-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OFD1	ENST00000340096.11	TSL:1 MANE Select	c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 23	ENSP00000344314.6	O75665-1
	OFD1	ENST00000380550.6	TSL:1	c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 22	ENSP00000369923.3	O75665-3
	OFD1	ENST00000922714.1		c.400_403delGAAA	p.Glu134IlefsTer10	frameshift	Exon 5 of 23	ENSP00000592773.1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Joubert syndrome 10 (1)
1	-	-	Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 (1)
1	-	-	Orofaciodigital syndrome I;C5979921:Joubert syndrome (1)
1	-	-	Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs312262830; hg19: chrX-13757135;