rs886037838

Variant names:

• chr14-75103841-C-A
• rs886037838
• NM_033116.6:c.1731+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_033116.6(NEK9):​c.1731+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK9 NM_033116.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

Genes affected

NEK9 (HGNC:18591): (NIMA related kinase 9) This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein is activated in mitosis and, in turn, activates other family members during mitosis. This protein also mediates cellular processes that are essential for interphase progression. [provided by RefSeq, Jul 2016]

ZC2HC1C (HGNC:20354): (zinc finger C2HC-type containing 1C) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZC2HC1C Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053061225 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033116.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	NM_033116.6	MANE Select	c.1731+1G>T		splice_donor intron	N/A	NP_149107.4
	NEK9	NM_001329237.2		c.1767+1G>T		splice_donor intron	N/A	NP_001316166.1
	NEK9	NM_001329238.2		c.1377+1G>T		splice_donor intron	N/A	NP_001316167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	ENST00000238616.10	TSL:1 MANE Select	c.1731+1G>T		splice_donor intron	N/A	ENSP00000238616.5
	NEK9	ENST00000553823.6	TSL:5	c.1732G>T	p.Val578Leu	missense	Exon 14 of 14	ENSP00000452537.2
	NEK9	ENST00000678037.1		c.1767+1G>T		splice_donor intron	N/A	ENSP00000504620.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		4.8
GERP RS		5.8
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -47
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs886037838; hg19: chr14-75570544;