15-89629561-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_198525.3(KIF7):c.3331C>T(p.Arg1111Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,606,422 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
KIF7
NM_198525.3 stop_gained
NM_198525.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 6.17
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]
TICRR (HGNC:28704): (TOPBP1 interacting checkpoint and replication regulator) Enables chromatin binding activity. Involved in regulation of DNA-dependent DNA replication initiation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
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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 15-89629561-G-A is Pathogenic according to our data. Variant chr15-89629561-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89629561-G-A is described in Lovd as [Pathogenic]. Variant chr15-89629561-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIF7 | NM_198525.3 | c.3331C>T | p.Arg1111Ter | stop_gained | 17/19 | ENST00000394412.8 | NP_940927.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF7 | ENST00000394412.8 | c.3331C>T | p.Arg1111Ter | stop_gained | 17/19 | 5 | NM_198525.3 | ENSP00000377934 | P2 | |
TICRR | ENST00000561095.1 | c.*228G>A | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 1 | ENSP00000453922 | ||||
KIF7 | ENST00000696512.1 | c.3454C>T | p.Arg1152Ter | stop_gained | 17/19 | ENSP00000512678 | A2 | |||
KIF7 | ENST00000677187.1 | n.1005C>T | non_coding_transcript_exon_variant | 5/7 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000408 AC: 1AN: 245338Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133318
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1454266Hom.: 0 Cov.: 37 AF XY: 0.00000967 AC XY: 7AN XY: 723860
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acrocallosal syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | research | Rare Disease Group, Clinical Genetics, Karolinska Institutet | Mar 12, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 23, 2022 | This premature translational stop signal has been observed in individual(s) with clinical features of KIF7-related conditions (PMID: 23125460, 27081521). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217670). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg1111*) in the KIF7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIF7 are known to be pathogenic (PMID: 19666503, 21552264, 21633164, 26648833). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Sep 22, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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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