14-75084618-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033116.6(NEK9):c.2886A>C(p.Leu962Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,614,188 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (15 hom.)
• Consequence: NEK9 NM_033116.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005352944).
• BP6: Variant 14-75084618-T-G is Benign according to our data. Variant chr14-75084618-T-G is described in ClinVar as [Benign]. Clinvar id is 710039.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00995 (1516/152326) while in subpopulation AFR AF= 0.032 (1330/41558). AF 95% confidence interval is 0.0306. There are 20 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK9	NM_033116.6	c.2886A>C	p.Leu962Phe	missense_variant	22/22	ENST00000238616.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK9	ENST00000238616.10	c.2886A>C	p.Leu962Phe	missense_variant	22/22	1	NM_033116.6	P1

Frequencies

GnomAD3 genomes AF: 0.00991 AC: 1508 AN: 152208 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00339 AC: 853 AN: 251362 Hom.: 5 AF XY: 0.00265 AC XY: 360 AN XY: 135866

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00140 AC: 2053 AN: 1461862 Hom.: 15 Cov.: 38 AF XY: 0.00141 AC XY: 1025 AN XY: 727234

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00995 AC: 1516 AN: 152326 Hom.: 20 Cov.: 32 AF XY: 0.00914 AC XY: 681 AN XY: 74484

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00221 Hom.: 5

Bravo AF: 0.0113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00397 AC: 482

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Benign	0.048
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.18
Sift	Benign	0.048	D
Sift4G	Uncertain	0.059	T
Polyphen		0.74	P
Vest4		0.29
MutPred		0.092		Loss of stability (P = 0.1069);
MVP		0.75
MPC		0.57
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.054
gMVP		0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61745420; hg19: chr14-75551321;