rs797044465
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_198525.3(KIF7):c.217del(p.Ala73ProfsTer109) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A73A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Consequence
KIF7
NM_198525.3 frameshift
NM_198525.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.314
Genes affected
KIF7 (HGNC:30497): (kinesin family member 7) This gene encodes a cilia-associated protein belonging to the kinesin family. This protein plays a role in the sonic hedgehog (SHH) signaling pathway through the regulation of GLI transcription factors. It functions as a negative regulator of the SHH pathway by preventing inappropriate activation of GLI2 in the absence of ligand, and as a positive regulator by preventing the processing of GLI3 into its repressor form. Mutations in this gene have been associated with various ciliopathies. [provided by RefSeq, Oct 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 15-89652713-GC-G is Pathogenic according to our data. Variant chr15-89652713-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 30900.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF7 | NM_198525.3 | c.217del | p.Ala73ProfsTer109 | frameshift_variant | 2/19 | ENST00000394412.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.217del | p.Ala73ProfsTer109 | frameshift_variant | 2/19 | 5 | NM_198525.3 | P2 | |
KIF7 | ENST00000445906.1 | c.217del | p.Ala73ProfsTer61 | frameshift_variant, NMD_transcript_variant | 2/5 | 1 | |||
KIF7 | ENST00000696512.1 | c.340del | p.Ala114ProfsTer109 | frameshift_variant | 2/19 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 24, 2016 | The c.217delG variant in the KIF7 gene has been reported previously in the homozygous state in two related individuals with Joubert syndrome (Dafinger et al., 2011). This variant causes a frameshift starting with codon Alanine 73, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 109 of the new reading frame, denoted p.Ala73ProfsX109. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.217delG variant was not observed in approximately 2300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.217delG as a pathogenic variant. - |
Joubert syndrome 12 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2011 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at