13-52144720-G-C

Position:

• chr13-52144720-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002498.3(NEK3):​c.775C>G​(p.Arg259Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000969 in 1,613,792 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (12 hom.)
• Consequence: NEK3 NM_002498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41

Genes affected

NEK3 (HGNC:7746): (NIMA related kinase 3) This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein differs from other NimA family members in that it is not cell cycle regulated and is found primarily in the cytoplasm. The kinase is activated by prolactin stimulation, leading to phosphorylation of VAV2 guanine nucleotide exchange factor, paxillin, and activation of the RAC1 GTPase. Two functional alleles for this gene have been identified in humans. The reference genome assembly (GRCh38) represents a functional allele that is associated with the inclusion of an additional coding exon in protein-coding transcripts, compared to an alternate functional allele that lacks the exon. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0093925595).
• BP6: Variant 13-52144720-G-C is Benign according to our data. Variant chr13-52144720-G-C is described in ClinVar as [Benign]. Clinvar id is 716994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000651 (951/1461646) while in subpopulation AFR AF= 0.0175 (585/33478). AF 95% confidence interval is 0.0163. There are 12 homozygotes in gnomad4_exome. There are 441 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK3	NM_002498.3	c.775C>G	p.Arg259Gly	missense_variant	9/16	ENST00000610828.5
NEK3	NM_152720.3	c.775C>G	p.Arg259Gly	missense_variant	9/16
NEK3	NR_164641.1	n.887C>G		non_coding_transcript_exon_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK3	ENST00000610828.5	c.775C>G	p.Arg259Gly	missense_variant	9/16	1	NM_002498.3	P2
NEK3	ENST00000618534.4	c.775C>G	p.Arg259Gly	missense_variant	9/16	5		P2
NEK3	ENST00000620675.4	c.775C>G	p.Arg259Gly	missense_variant	9/16	5		A2
NEK3	ENST00000617054.1	c.775C>G	p.Arg259Gly	missense_variant, NMD_transcript_variant	8/14	5

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 609 AN: 152028 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00131 AC: 327 AN: 249188 Hom.: 1 AF XY: 0.00106 AC XY: 143 AN XY: 135190

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000651 AC: 951 AN: 1461646 Hom.: 12 Cov.: 31 AF XY: 0.000607 AC XY: 441 AN XY: 727102

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152146 Hom.: 3 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74376

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000586 Hom.: 0

Bravo AF: 0.00479

ESP6500AA AF: 0.0146 AC: 57

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.00157 AC: 190

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	.;.;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T;T;T;.
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.0040	.;.;B;B
Vest4		0.35
MVP		0.14
ClinPred		0.016	T
GERP RS		2.6
Varity_R		0.081
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34077016; hg19: chr13-52718855;