1-198297228-C-G

Position:

• chr1-198297228-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_133494.3(NEK7):​c.786C>G​(p.His262Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK7 NM_133494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

Genes affected

NEK7 (HGNC:13386): (NIMA related kinase 7) NIMA-related kinases share high amino acid sequence identity with the gene product of the Aspergillus nidulans 'never in mitosis A' gene, which controls initiation of mitosis.[supplied by OMIM, Jul 2002]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Does not affect interaction with NEK9. (size 0) in uniprot entity NEK7_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK7	NM_133494.3	c.786C>G	p.His262Gln	missense_variant	9/10	ENST00000367385.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK7	ENST00000367385.9	c.786C>G	p.His262Gln	missense_variant	9/10	5	NM_133494.3	P1
NEK7	ENST00000538004.5	c.786C>G	p.His262Gln	missense_variant	9/10	1		P1
NEK7	ENST00000493790.1	n.671C>G		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.786C>G (p.H262Q) alteration is located in exon 9 (coding exon 8) of the NEK7 gene. This alteration results from a C to G substitution at nucleotide position 786, causing the histidine (H) at amino acid position 262 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.082	T;T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.45	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.13
Sift	Benign	0.32	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.13	B;B
Vest4		0.66
MutPred		0.36		Gain of glycosylation at P257 (P = 0.1228);Gain of glycosylation at P257 (P = 0.1228);
MVP		0.71
MPC		0.63
ClinPred		0.54	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs761363477; hg19: chr1-198266358;