dbSNP rs2271395: 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:

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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

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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