Genetic Variant NEK9:p.Ile167Thr (chr14-75120534-A-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_033116.6(NEK9):c.500T>C(p.Ile167Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NEK9
NM_033116.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.70

Publications

0 publications found

Variant links:

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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

NEK9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 14-75120534-A-G is Pathogenic according to our data. Variant chr14-75120534-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 243002.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK9	NM_033116.6	MANE Select	c.500T>C	p.Ile167Thr	missense	Exon 4 of 22	NP_149107.4
NEK9	NM_001329237.2		c.500T>C	p.Ile167Thr	missense	Exon 4 of 22	NP_001316166.1
NEK9	NM_001329238.2		c.146T>C	p.Ile49Thr	missense	Exon 4 of 22	NP_001316167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEK9	ENST00000238616.10	TSL:1 MANE Select	c.500T>C	p.Ile167Thr	missense	Exon 4 of 22	ENSP00000238616.5
NEK9	ENST00000678037.1		c.500T>C	p.Ile167Thr	missense	Exon 4 of 22	ENSP00000504620.1
NEK9	ENST00000678531.1		c.146T>C	p.Ile49Thr	missense	Exon 4 of 22	ENSP00000503827.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nevus comedonicus syndrome

Pathogenic:1

Jul 12, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.7

PhyloP100

8.7

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.96

MutPred

0.85

Loss of stability (P = 0.028)

MVP

0.90

MPC

2.3

ClinPred

0.98

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.83

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over