rs780247729
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_178170.3(NEK8):c.889+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_178170.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEK8 | NM_178170.3 | c.889+1G>T | splice_donor_variant | ENST00000268766.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEK8 | ENST00000268766.11 | c.889+1G>T | splice_donor_variant | 1 | NM_178170.3 | P1 | |||
ENST00000584779.1 | n.417+4612C>A | intron_variant, non_coding_transcript_variant | 5 | ||||||
NEK8 | ENST00000592510.1 | c.449+1G>T | splice_donor_variant | 3 | |||||
NEK8 | ENST00000543014.1 | c.1049+1G>T | splice_donor_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135008
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 727232
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Nephronophthisis 9;C3809434:Renal-hepatic-pancreatic dysplasia 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 27, 2021 | - - |
Nephronophthisis 9 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2017 | Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEK8 are known to be pathogenic (PMID: 23418306). This variant has not been reported in the literature in individuals with NEK8-related disease. This variant is present in population databases (rs780247729, ExAC 0.002%). This sequence change affects a donor splice site in intron 6 of the NEK8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at