dbSNP rs794001: N4BP2:p.Asp611Asn (chr4-40119942-G-A) – 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.1831G>A(p.Asp611Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,381,106 control chromosomes in the GnomAD database, including 414,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.76 ( 44756 hom., cov: 32)

Exomes 𝑓: 0.77 ( 369249 hom. )

Consequence

N4BP2
NM_018177.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.913

Publications

31 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=6.5597726E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
N4BP2	NM_018177.6 link	c.1831G>A	p.Asp611Asn	missense_variant	Exon 9 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.1831G>A	p.Asp611Asn	missense_variant	Exon 9 of 18	5	NM_018177.6	ENSP00000261435.6		Q86UW6-1

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116107

AN:

151920

Hom.:

44729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.685

Gnomad AMI

AF:

0.809

Gnomad AMR

AF:

0.823

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.968

Gnomad SAS

AF:

0.932

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.765

Gnomad OTH

AF:

0.776

GnomAD2 exomes

AF:

0.810

AC:

158083

AN:

195264

AF XY:

0.813

show subpopulations

Gnomad AFR exome

AF:

0.681

Gnomad AMR exome

AF:

0.884

Gnomad ASJ exome

AF:

0.776

Gnomad EAS exome

AF:

0.967

Gnomad FIN exome

AF:

0.793

Gnomad NFE exome

AF:

0.767

Gnomad OTH exome

AF:

0.791

GnomAD4 exome

AF:

0.772

AC:

949229

AN:

1229068

Hom.:

369249

Cov.:

AF XY:

0.778

AC XY:

479233

AN XY:

616012

show subpopulations

African (AFR)

AF:

0.671

AC:

18404

AN:

27444

American (AMR)

AF:

0.874

AC:

26834

AN:

30714

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

15977

AN:

20756

East Asian (EAS)

AF:

0.962

AC:

36882

AN:

38320

South Asian (SAS)

AF:

0.927

AC:

63945

AN:

68944

European-Finnish (FIN)

AF:

0.795

AC:

40382

AN:

50786

Middle Eastern (MID)

AF:

0.764

AC:

3097

AN:

4054

European-Non Finnish (NFE)

AF:

0.751

AC:

703389

AN:

936436

Other (OTH)

AF:

0.781

AC:

40319

AN:

51614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

8525

17051

25576

34102

42627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16382

32764

49146

65528

81910

<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:

0.764

AC:

116192

AN:

152038

Hom.:

44756

Cov.:

AF XY:

0.770

AC XY:

57247

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.685

AC:

28393

AN:

41448

American (AMR)

AF:

0.823

AC:

12583

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

2669

AN:

3468

East Asian (EAS)

AF:

0.968

AC:

5025

AN:

5192

South Asian (SAS)

AF:

0.931

AC:

4491

AN:

4822

European-Finnish (FIN)

AF:

0.799

AC:

8425

AN:

10546

Middle Eastern (MID)

AF:

0.796

AC:

234

AN:

294

European-Non Finnish (NFE)

AF:

0.765

AC:

52004

AN:

67964

Other (OTH)

AF:

0.774

AC:

1630

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1385

2771

4156

5542

6927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.773

Hom.:

136460

Bravo

AF:

0.759

ESP6500AA

AF:

0.692

AC:

2967

ESP6500EA

AF:

0.773

AC:

6549

ExAC

AF:

0.811

AC:

97739

Asia WGS

AF:

0.900

AC:

3123

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.00061

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.21

MetaRNN

Benign

6.6e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

PhyloP100

0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

1.0

REVEL

Benign

0.067

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.032

MPC

0.075

ClinPred

0.000021

GERP RS

0.47

Varity_R

0.035

gMVP

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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