14-75120533-GA-CG

Variant names:

• chr14-75120533-GA-CG
• NM_033116.6:c.500_501delTCinsCG
• NEK9 p.Ile167Thr

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_033116.6(NEK9):​c.500_501delTCinsCG​(p.Ile167Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK9 NM_033116.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.70
• 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]

NEK9 Gene-Disease associations (from GenCC):

• NEK9-related lethal skeletal dysplasia

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_033116.6 (NEK9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	NM_033116.6	MANE Select	c.500_501delTCinsCG	p.Ile167Thr	missense	N/A	NP_149107.4
	NEK9	NM_001329237.2		c.500_501delTCinsCG	p.Ile167Thr	missense	N/A	NP_001316166.1	A0A7I2V5R1
	NEK9	NM_001329238.2		c.146_147delTCinsCG	p.Ile49Thr	missense	N/A	NP_001316167.1	A0A7I2V454

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK9	ENST00000238616.10	TSL:1 MANE Select	c.500_501delTCinsCG	p.Ile167Thr	missense	N/A	ENSP00000238616.5	Q8TD19
	NEK9	ENST00000678037.1		c.500_501delTCinsCG	p.Ile167Thr	missense	N/A	ENSP00000504620.1	A0A7I2V5R1
	NEK9	ENST00000909801.1		c.500_501delTCinsCG	p.Ile167Thr	missense	N/A	ENSP00000579860.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-75587236;