rs202229910
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_198525.3(KIF7):c.2917C>T(p.Arg973Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000045 in 1,555,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000036 ( 0 hom. )
Consequence
KIF7
NM_198525.3 stop_gained
NM_198525.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.66
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 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 15-89631689-G-A is Pathogenic according to our data. Variant chr15-89631689-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89631689-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIF7 | NM_198525.3 | c.2917C>T | p.Arg973Ter | stop_gained | 15/19 | ENST00000394412.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.2917C>T | p.Arg973Ter | stop_gained | 15/19 | 5 | NM_198525.3 | P2 | |
KIF7 | ENST00000696512.1 | c.3040C>T | p.Arg1014Ter | stop_gained | 15/19 | A2 | |||
KIF7 | ENST00000677187.1 | n.591C>T | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000123 AC: 2AN: 162808Hom.: 0 AF XY: 0.0000115 AC XY: 1AN XY: 86662
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GnomAD4 exome AF: 0.00000356 AC: 5AN: 1403296Hom.: 0 Cov.: 39 AF XY: 0.00000433 AC XY: 3AN XY: 692554
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74362
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acrocallosal syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2018 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KIF7 are known to be pathogenic (PMID: 19666503, 21552264, 21633164, 26648833). This variant has been observed in an individual affected with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217671). This variant is present in population databases (rs202229910, ExAC 0.1%). This sequence change creates a premature translational stop signal (p.Arg973*) in the KIF7 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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