rs1085307854

Variant names:

• chr1-200559407-T-G
• rs1085307854
• NM_014875.3:c.4276A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 15/22 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.304
• Publications: 0 publications found

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]

KIF14 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• microcephaly 20, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
KIF14	NM_014875.3	c.4276A>C	p.Lys1426Gln	missense_variant	Exon 27 of 30	ENST00000367350.5	NP_055690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF14	ENST00000367350.5	c.4276A>C	p.Lys1426Gln	missense_variant	Exon 27 of 30	2	NM_014875.3	ENSP00000356319.4
KIF14	ENST00000614960.4	c.4276A>C	p.Lys1426Gln	missense_variant	Exon 26 of 29	1		ENSP00000483069.1

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

Submissions by phenotype

not provided Uncertain:1

Mar 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 26, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

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: 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
PhyloP100		0.30
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1085307854; hg19: chr1-200528535;