dbSNP rs794001: N4BP2:p.Asp611Asn (chr4-40119942-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.810

AC:

158083

AN:

195264

Hom.:

64685

AF XY:

0.813

AC XY:

85899

AN XY:

105626

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 SAS exome

AF:

0.929

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

Gnomad4 AFR exome

AF:

0.671

Gnomad4 AMR exome

AF:

0.874

Gnomad4 ASJ exome

AF:

0.770

Gnomad4 EAS exome

AF:

0.962

Gnomad4 SAS exome

AF:

0.927

Gnomad4 FIN exome

AF:

0.795

Gnomad4 NFE exome

AF:

0.751

Gnomad4 OTH exome

AF:

0.781

GnomAD4 genome

AF:

0.764

AC:

116192

AN:

152038

Hom.:

44756

Cov.:

AF XY:

0.770

AC XY:

57247

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.685

Gnomad4 AMR

AF:

0.823

Gnomad4 ASJ

AF:

0.770

Gnomad4 EAS

AF:

0.968

Gnomad4 SAS

AF:

0.931

Gnomad4 FIN

AF:

0.799

Gnomad4 NFE

AF:

0.765

Gnomad4 OTH

AF:

0.774

Alfa

AF:

0.776

Hom.:

95782

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over