Genetic Variant N4BP2:p.Asp611Tyr (chr4-40119942-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018177.6(N4BP2):c.1831G>T(p.Asp611Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050227135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018177.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	NM_018177.6	MANE Select	c.1831G>T	p.Asp611Tyr	missense	Exon 9 of 18	NP_060647.2
	N4BP2	NM_001318359.2		c.1591G>T	p.Asp531Tyr	missense	Exon 10 of 19	NP_001305288.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
N4BP2	ENST00000261435.11	TSL:5 MANE Select	c.1831G>T	p.Asp611Tyr	missense	Exon 9 of 18	ENSP00000261435.6	Q86UW6-1
N4BP2	ENST00000513269.1	TSL:1	c.769G>T	p.Asp257Tyr	missense	Exon 6 of 15	ENSP00000426430.1	H0YA93
N4BP2	ENST00000511480.5	TSL:1	n.*1622G>T		non_coding_transcript_exon	Exon 10 of 19	ENSP00000422436.1	D6RC09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1234634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

618638

African (AFR)

AF:

0.00

AC:

AN:

27576

American (AMR)

AF:

0.00

AC:

AN:

30734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20792

East Asian (EAS)

AF:

0.00

AC:

AN:

38324

South Asian (SAS)

AF:

0.00

AC:

AN:

68988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

941508

Other (OTH)

AF:

0.00

AC:

AN:

51830

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0012

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.44

M_CAP

Benign

0.0078

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.94

REVEL

Benign

0.027

Sift

Uncertain

0.0080

Sift4G

Benign

0.073

Polyphen

0.20

Vest4

0.15

MutPred

0.16

Gain of glycosylation at S616 (P = 0.014)

MVP

0.28

MPC

0.095

ClinPred

0.093

GERP RS

0.47

Varity_R

0.093

gMVP

0.35

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over