rs1085307854

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

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.304
Variant links:
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
KIF14NM_014875.3 linkuse as main transcriptc.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
KIF14ENST00000367350.5 linkuse as main transcriptc.4276A>C p.Lys1426Gln missense_variant 27/302 NM_014875.3 ENSP00000356319 P1
KIF14ENST00000614960.4 linkuse as main transcriptc.4276A>C p.Lys1426Gln missense_variant 26/291 ENSP00000483069 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
27
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 submitterclinical testingGeneDxMar 28, 2017The 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 submitterclinical testing;provider interpretationGeisinger Autism and Developmental Medicine Institute, Geisinger Health SystemFeb 26, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
11
DANN
Uncertain
0.98
DEOGEN2
Benign
0.033
T;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.53
T;.
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.060
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
0.84
N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.1
.;N
REVEL
Benign
0.057
Sift
Benign
0.16
.;T
Sift4G
Benign
0.29
T;T
Polyphen
0.070
B;B
Vest4
0.19
MutPred
0.30
Loss of ubiquitination at K1426 (P = 0.0071);Loss of ubiquitination at K1426 (P = 0.0071);
MVP
0.67
MPC
0.088
ClinPred
0.40
T
GERP RS
4.5
Varity_R
0.075
gMVP
0.10

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1085307854; hg19: chr1-200528535; API