1-200589214-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
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
Consequence
NM_014875.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
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
GnomAD3 exomes AF: 0.0000212 AC: 5AN: 235902Hom.: 0 AF XY: 0.00000784 AC XY: 1AN XY: 127510
GnomAD4 exome AF: 0.00000763 AC: 11AN: 1441086Hom.: 0 Cov.: 27 AF XY: 0.00000558 AC XY: 4AN XY: 716916
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly 20, primary, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at