3-52711865-C-T

Position:

• chr3-52711865-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003157.6(NEK4):​c.2438G>A​(p.Arg813His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,583,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: NEK4 NM_003157.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0690

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010242075).
• BP6: Variant 3-52711865-C-T is Benign according to our data. Variant chr3-52711865-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2356215.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK4	NM_003157.6	c.2438G>A	p.Arg813His	missense_variant	16/16	ENST00000233027.10	NP_003148.2
NEK4	NM_001348412.2	c.2300G>A	p.Arg767His	missense_variant	15/15		NP_001335341.1
NEK4	NM_001348414.2	c.2192G>A	p.Arg731His	missense_variant	16/16		NP_001335343.1
NEK4	NM_001193533.3	c.2171G>A	p.Arg724His	missense_variant	15/15		NP_001180462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK4	ENST00000233027.10	c.2438G>A	p.Arg813His	missense_variant	16/16	1	NM_003157.6	ENSP00000233027.5
NEK4	ENST00000535191.5	c.2171G>A	p.Arg724His	missense_variant	15/15	2		ENSP00000437703.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000465 AC: 114 AN: 245336 Hom.: 0 AF XY: 0.000564 AC XY: 75 AN XY: 132906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000668

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000926

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000379 AC: 543 AN: 1430962 Hom.: 0 Cov.: 24 AF XY: 0.000426 AC XY: 304 AN XY: 713386

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.000691

Gnomad4 ASJ exome AF: 0.00194

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000784

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.87
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.44	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.090
Sift	Benign	0.34	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0050	B;.
Vest4		0.047
MVP		0.44
MPC		0.18
ClinPred		0.017	T
GERP RS		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs182485847; hg19: chr3-52745881;