3-52763618-G-T

Variant names:

• chr3-52763618-G-T
• rs1029871
• NM_003157.6:c.673C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003157.6(NEK4):​c.673C>A​(p.Pro225Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEK4 NM_003157.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.65
• Publications: 51 publications found

Genes affected

NEK4 (HGNC:11399): (NIMA related kinase 4) The protein encoded by this gene is a serine/threonine protein kinase required for normal entry into replicative senescence. The encoded protein also is involved in cell cycle arrest in response to double-stranded DNA damage. Finally, this protein plays a role in maintaining cilium integrity, and defects in this gene have been associated with ciliopathies. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003157.6. 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
	NEK4	NM_003157.6	MANE Select	c.673C>A	p.Pro225Thr	missense	Exon 5 of 16	NP_003148.2
	NEK4	NM_001348412.2		c.673C>A	p.Pro225Thr	missense	Exon 5 of 15	NP_001335341.1
	NEK4	NM_001348413.2		c.673C>A	p.Pro225Thr	missense	Exon 5 of 14	NP_001335342.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK4	ENST00000233027.10	TSL:1 MANE Select	c.673C>A	p.Pro225Thr	missense	Exon 5 of 16	ENSP00000233027.5
	NEK4	ENST00000383721.8	TSL:1	c.673C>A	p.Pro225Thr	missense	Exon 5 of 14	ENSP00000373227.4
	NEK4	ENST00000535191.5	TSL:2	c.406C>A	p.Pro136Thr	missense	Exon 4 of 15	ENSP00000437703.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432884 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 711018

African (AFR) AF: 0.00 AC: 0 AN: 32252

American (AMR) AF: 0.00 AC: 0 AN: 38930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.00 AC: 0 AN: 81602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5218

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098068

Other (OTH) AF: 0.00 AC: 0 AN: 59236

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.011	D
Sift4G	Benign	0.076	T
Polyphen		0.96	D
Vest4		0.37
MutPred		0.34		Loss of catalytic residue at P224 (P = 0.0142)
MVP		0.29
MPC		0.66
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.56
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1029871; hg19: chr3-52797634;