1-200589214-T-G

Variant names:

• chr1-200589214-T-G
• rs776623187
• NM_014875.3:c.3114+3A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014875.3(KIF14):​c.3114+3A>C variant causes a splice 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.262
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 rank	MANE	Protein	UniProt
KIF14	NM_014875.3	c.3114+3A>C		splice_region_variant, intron_variant	Intron 18 of 29	ENST00000367350.5	NP_055690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF14	ENST00000367350.5	c.3114+3A>C		splice_region_variant, intron_variant	Intron 18 of 29	2	NM_014875.3	ENSP00000356319.4
KIF14	ENST00000614960.4	c.3114+3A>C		splice_region_variant, intron_variant	Intron 17 of 28	1		ENSP00000483069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 235902 AF XY: 0.00000784

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32208

American (AMR) AF: 0.00 AC: 0 AN: 40992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.000121 AC: 10 AN: 82328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102586

Other (OTH) AF: 0.0000168 AC: 1 AN: 59562

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 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).

Microcephaly 20, primary, autosomal recessive Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed splice region c.3114+3A>C variant in KIF14 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The c.3114+3A>C variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. SpliceAI predicts this variant to cause splice donor loss (0.94). Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). In absence of another reportable variant in KIF14 gene, the molecular diagnosis is not confirmed.

not provided Uncertain:1

Mar 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs776623187; hg19: chr1-200558342;