13-52144720-G-C

Variant names:

• chr13-52144720-G-C
• rs34077016
• NM_002498.3:c.775C>G

Variant summary

Our verdict is Benign. The variant received -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. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 441 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK3	NM_002498.3	MANE Select	c.775C>G	p.Arg259Gly	missense	Exon 9 of 16	NP_002489.1	P51956-1
	NEK3	NM_001424264.1		c.793C>G	p.Arg265Gly	missense	Exon 9 of 16	NP_001411193.1
	NEK3	NM_001424265.1		c.775C>G	p.Arg259Gly	missense	Exon 9 of 16	NP_001411194.1	P51956-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK3	ENST00000610828.5	TSL:1 MANE Select	c.775C>G	p.Arg259Gly	missense	Exon 9 of 16	ENSP00000480328.1	P51956-1
	NEK3	ENST00000962649.1		c.793C>G	p.Arg265Gly	missense	Exon 8 of 15	ENSP00000632708.1
	NEK3	ENST00000618534.4	TSL:5	c.775C>G	p.Arg259Gly	missense	Exon 9 of 16	ENSP00000484443.1	P51956-1

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

GnomAD2 exomes AF: 0.00131 AC: 327 AN: 249188 AF XY: 0.00106

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 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

African (AFR) AF: 0.0175 AC: 585 AN: 33478

American (AMR) AF: 0.00145 AC: 65 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111852

Other (OTH) AF: 0.00190 AC: 115 AN: 60368

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

African (AFR) AF: 0.0133 AC: 551 AN: 41520

American (AMR) AF: 0.00242 AC: 37 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.24	T
Sift4G	Uncertain	0.031	D
Polyphen		0.0040	B
Vest4		0.35
MVP		0.14
ClinPred		0.016	T
GERP RS		2.6
Varity_R		0.081
gMVP		0.40
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs34077016; hg19: chr13-52718855;