rs1085307854
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_014875.3(KIF14):c.4276A>C(p.Lys1426Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
KIF14
NM_014875.3 missense
NM_014875.3 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 0.304
Genes affected
KIF14 (HGNC:19181): (kinesin family member 14) This gene encodes a member of the kinesin-3 superfamily of microtubule motor proteins. These proteins are involved in numerous processes including vesicle transport, chromosome segregation, mitotic spindle formation, and cytokinesis. In human HeLa-S3 and 293T cells, this protein is localized to the cytoplasm during interphase, to the spindle poles and spindle microtubules during mitosis, and to the midbody during cytokinesis. An internal motor domain displays microtubule-dependent ATPase activity, consistent with its function as a microtubule motor protein. Knockdown of this gene results in failed cytokinesis with endoreplication, which results in multinucleated cells. This gene has been identified as a likely oncogene in breast, lung and ovarian cancers, as well as retinoblastomas and gliomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.060499668).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KIF14 | NM_014875.3 | c.4276A>C | p.Lys1426Gln | missense_variant | 27/30 | ENST00000367350.5 | NP_055690.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KIF14 | ENST00000367350.5 | c.4276A>C | p.Lys1426Gln | missense_variant | 27/30 | 2 | NM_014875.3 | ENSP00000356319 | P1 | |
KIF14 | ENST00000614960.4 | c.4276A>C | p.Lys1426Gln | missense_variant | 26/29 | 1 | ENSP00000483069 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2017 | The K1426Q variant in the KIF14 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K1426Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K1426Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K1426Q as a variant of uncertain significance. - |
Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Feb 26, 2018 | This 4 year old male has a history of global developmental delay, microcephaly, autism spectrum disorder, dysmorphic features, and hearing impairment. The patient is compound heterozygous for variants in KIF14. The c.4276A>C variant is absent from population databases (ExAC and gnomAD). Computational models are inconsistent. Homozygous and compound heteroxygous pathogenic variants have been reported in individuals with autosomal recessive Meckel syndrome 12, clinical features of which include intrauterine growth restriction, microcephaly, cerebellar hypoplasia, renal agenesis/hypoplasia, ureteral hypoplasia, uterine hypoplasia, and flexion arthrogryposis (Filges et al. 2014). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;.
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Benign
.;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Loss of ubiquitination at K1426 (P = 0.0071);Loss of ubiquitination at K1426 (P = 0.0071);
MVP
MPC
0.088
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at