rs2271395

chr4-40137056-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 12/19 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.053 (643 hom., cov: 32)
  • Exomes 𝑓: 0.059 (6377 hom.)
• Consequence: N4BP2 NM_018177.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
N4BP2	NM_018177.6	c.4759A>G	p.Thr1587Ala	missense_variant	14/18	ENST00000261435.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
N4BP2	ENST00000261435.11	c.4759A>G	p.Thr1587Ala	missense_variant	14/18	5	NM_018177.6	P1
N4BP2	ENST00000513269.1	c.3700A>G	p.Thr1234Ala	missense_variant	11/15	1
N4BP2	ENST00000511480.5	c.*4550A>G		3_prime_UTR_variant, NMD_transcript_variant	15/19	1
N4BP2	ENST00000706658.1	c.*4550A>G		3_prime_UTR_variant, NMD_transcript_variant	17/21

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8070 AN: 152152 Hom.: 643 Cov.: 32

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

GnomAD3 exomes AF: 0.0862 AC: 21644 AN: 251196 Hom.: 2298 AF XY: 0.0888 AC XY: 12058 AN XY: 135780

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 SAS exome AF: 0.147

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.: 31 AF XY: 0.0626 AC XY: 45502 AN XY: 726642

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.0748

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.0405

Gnomad4 OTH exome AF: 0.0690

GnomAD4 genome AF: 0.0530 AC: 8070 AN: 152270 Hom.: 643 Cov.: 32 AF XY: 0.0564 AC XY: 4200 AN XY: 74466

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.0689

Gnomad4 EAS AF: 0.406

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0423

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0593 Hom.: 995

Bravo AF: 0.0550

TwinsUK AF: 0.0413 AC: 153

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.0193 AC: 85

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	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	11
Dann	Benign	0.97
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.025
Sift	Uncertain	0.020	D
Sift4G	Benign	0.11	T
Polyphen		0.28	B
Vest4		0.069
MPC		0.080
ClinPred		0.0043	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs2271395; hg19: chr4-40138676; COSMIC: COSV54700325;