chr1-200589214-T-G

Position:

• chr1-200589214-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014875.3(KIF14):​c.3114+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000763 in 1,441,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: KIF14 NM_014875.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.262

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF14	NM_014875.3	c.3114+3A>C		splice_donor_region_variant, intron_variant		ENST00000367350.5	NP_055690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF14	ENST00000367350.5	c.3114+3A>C		splice_donor_region_variant, intron_variant		2	NM_014875.3	ENSP00000356319	P1
KIF14	ENST00000614960.4	c.3114+3A>C		splice_donor_region_variant, intron_variant		1		ENSP00000483069	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000212 AC: 5 AN: 235902 Hom.: 0 AF XY: 0.00000784 AC XY: 1 AN XY: 127510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000763 AC: 11 AN: 1441086 Hom.: 0 Cov.: 27 AF XY: 0.00000558 AC XY: 4 AN XY: 716916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2017

The c.3114+3A>C variant in the KIF14 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to damage or destroy the splice donor site in intron 18, and is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.3114+3A>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.3114+3A>C 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 variant is present at a frequency of 0.018% in the South Asian population in ExAC and gnomAD. Computational models predict this variant to damage or destroy the splice donor site in intron 18 and result in abnormal gene splicing. Homozygous and compound heterozygous 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
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs776623187; hg19: chr1-200558342;