Genetic Variant N4BP2:p.Thr1587Ala (chr4-40137056-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018177.6(N4BP2):c.4759A>G(p.Thr1587Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 1,612,904 control chromosomes in the GnomAD database, including 7,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.053 ( 643 hom., cov: 32)

Exomes 𝑓: 0.059 ( 6377 hom. )

Consequence

N4BP2
NM_018177.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.788

Publications

21 publications found

Variant links:

Genes affected

N4BP2 (HGNC:29851): (NEDD4 binding protein 2) This gene encodes a protein containing a polynucleotide kinase domain (PNK) near the N-terminal region, and a Small MutS Related (Smr) domain near the C-terminal region. The encoded protein can bind to both B-cell leukemia/lymphoma 3 (BCL-3) and neural precursor cell expressed, developmentally downregulated 4, (Nedd4) proteins. This protein binds and hydrolyzes ATP, may function as a 5'-polynucleotide kinase, and has the capacity to be a ubiquitylation substrate. This protein may play a role in transcription-coupled DNA repair or genetic recombination. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

N4BP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002336949).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
N4BP2	NM_018177.6 link	c.4759A>G	p.Thr1587Ala	missense_variant	Exon 14 of 18	ENST00000261435.11	NP_060647.2	Q86UW6-1B2ZZ87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11 link	c.4759A>G	p.Thr1587Ala	missense_variant	Exon 14 of 18	5	NM_018177.6	ENSP00000261435.6		Q86UW6-1

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

8070

AN:

152152

Hom.:

643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.0516

Gnomad AMR

AF:

0.0557

Gnomad ASJ

AF:

0.0689

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.0665

GnomAD2 exomes

AF:

0.0862

AC:

21644

AN:

251196

AF XY:

0.0888

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0750

Gnomad ASJ exome

AF:

0.0724

Gnomad EAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.0232

Gnomad NFE exome

AF:

0.0425

Gnomad OTH exome

AF:

0.0780

GnomAD4 exome

AF:

0.0594

AC:

86819

AN:

1460634

Hom.:

6377

Cov.:

AF XY:

0.0626

AC XY:

45502

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.0164

AC:

548

AN:

33464

American (AMR)

AF:

0.0725

AC:

3240

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0748

AC:

1953

AN:

26114

East Asian (EAS)

AF:

0.439

AC:

17380

AN:

39616

South Asian (SAS)

AF:

0.148

AC:

12711

AN:

86108

European-Finnish (FIN)

AF:

0.0230

AC:

1228

AN:

53392

Middle Eastern (MID)

AF:

0.108

AC:

621

AN:

5762

European-Non Finnish (NFE)

AF:

0.0405

AC:

44973

AN:

1111134

Other (OTH)

AF:

0.0690

AC:

4165

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3393

6786

10179

13572

16965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1958

3916

5874

7832

9790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0530

AC:

8070

AN:

152270

Hom.:

643

Cov.:

AF XY:

0.0564

AC XY:

4200

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0180

AC:

747

AN:

41572

American (AMR)

AF:

0.0556

AC:

850

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0689

AC:

239

AN:

3468

East Asian (EAS)

AF:

0.406

AC:

2097

AN:

5164

South Asian (SAS)

AF:

0.158

AC:

762

AN:

4830

European-Finnish (FIN)

AF:

0.0259

AC:

275

AN:

10614

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0423

AC:

2878

AN:

68016

Other (OTH)

AF:

0.0701

AC:

148

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

353

706

1060

1413

1766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0559

Hom.:

1684

Bravo

AF:

0.0550

TwinsUK

AF:

0.0413

AC:

153

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.0459

AC:

395

ExAC

AF:

0.0862

AC:

10460

Asia WGS

AF:

0.236

AC:

821

AN:

3474

EpiCase

AF:

0.0538

EpiControl

AF:

0.0528

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0020

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PhyloP100

0.79

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.41

REVEL

Benign

0.025

Sift

Uncertain

0.020

Sift4G

Benign

0.11

Polyphen

0.28

Vest4

0.069

MPC

0.080

ClinPred

0.0043

GERP RS

2.9

Varity_R

0.038

gMVP

0.29

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over