rs2271395

Variant names:

• chr4-40137056-A-G
• rs2271395
• NM_018177.6:c.4759A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000261435.11(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 ENST00000261435.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788
• Publications: 21 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261435.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	NM_018177.6	MANE Select	c.4759A>G	p.Thr1587Ala	missense	Exon 14 of 18	NP_060647.2
	N4BP2	NM_001318359.2		c.4519A>G	p.Thr1507Ala	missense	Exon 15 of 19	NP_001305288.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	N4BP2	ENST00000261435.11	TSL:5 MANE Select	c.4759A>G	p.Thr1587Ala	missense	Exon 14 of 18	ENSP00000261435.6
	N4BP2	ENST00000513269.1	TSL:1	c.3697A>G	p.Thr1233Ala	missense	Exon 11 of 15	ENSP00000426430.1
	N4BP2	ENST00000511480.5	TSL:1	n.*4550A>G		non_coding_transcript_exon	Exon 15 of 19	ENSP00000422436.1

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

GnomAD2 exomes AF: 0.0862 AC: 21644 AN: 251196 AF XY: 0.0888

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

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

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

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: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0423 AC: 2878 AN: 68016

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

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: 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 v4.9

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
PhyloP100		0.79
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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