NM_003611.3:c.400_403delGAAA
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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
Consequence
NM_003611.3 frameshift
Scores
Clinical Significance
Conservation
Publications
- ciliopathyInheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
- Joubert syndrome 10Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- orofaciodigital syndrome IInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- retinitis pigmentosa 23Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- retinitis pigmentosaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- orofaciodigital syndrome type 6Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Simpson-Golabi-Behmel syndrome type 2Inheritance: XL Classification: LIMITED Submitted by: G2P
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Joubert syndrome;C1510460:Orofaciodigital syndrome I Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu134Ilefs*10) 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 premature translational stop signal has been observed in individual(s) with oral-facial-digital syndrome (PMID: 18546297). ClinVar contains an entry for this variant (Variation ID: 41117). For these reasons, this variant has been classified as Pathogenic. -
Joubert syndrome 10 Pathogenic:1
De novo variant in proband, maternity and paternity confirmed (PS2). Previously reported pathogenic in 2 manuscripts but unclear if same patient described (PMID: 18546297; PMID: 24884629). Protein truncating variants are a known disease mechainism (PVS1) and absent from gnomAD (PM2). -
Retinitis pigmentosa 23;C1510460:Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 Pathogenic:1
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Orofaciodigital syndrome I;C1846175:Simpson-Golabi-Behmel syndrome type 2;C2749019:Joubert syndrome 10 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at