3-131029746-G-T

Variant summary

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

The NM_024800.5(NEK11):c.38G>T(p.Gly13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEK11 NM_024800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.246

Genes affected

NEK11 (HGNC:18593): (NIMA related kinase 11) This gene encodes a member of the never in mitosis gene A family of kinases. The encoded protein localizes to the nucleoli, and may function with NEK2A in the S-phase checkpoint. The encoded protein appears to play roles in DNA replication and response to genotoxic stress. Alternatively spliced transcript variants have been described.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06627616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK11	NM_024800.5	c.38G>T	p.Gly13Val	missense_variant	3/18	ENST00000383366.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK11	ENST00000383366.9	c.38G>T	p.Gly13Val	missense_variant	3/18	1	NM_024800.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 16, 2022

The c.38G>T (p.G13V) alteration is located in exon 3 (coding exon 1) of the NEK11 gene. This alteration results from a G to T substitution at nucleotide position 38, causing the glycine (G) at amino acid position 13 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Benign	0.54
DEOGEN2	Benign	0.018	T;.;.;T;.;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.75	T;T;.;.;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.30	T;T;T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T;T;T
Polyphen		0.023	B;B;B;B;B;B;B
Vest4		0.16
MutPred		0.49		Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);Loss of glycosylation at S14 (P = 0.0528);
MVP		0.52
MPC		0.034
ClinPred		0.077	T
GERP RS		1.5
Varity_R		0.046
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2064498385; hg19: chr3-130748590;