rs794001

chr4-40119942-G-Achr4-40119942-G-Cchr4-40119942-G-T

Variant summary

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

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

• Frequency:
  • Genomes: 𝑓 0.76 (44756 hom., cov: 32)
  • Exomes 𝑓: 0.77 (369249 hom.)
• Consequence: N4BP2 NM_018177.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913

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=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/exons	MANE	UniProt
N4BP2	NM_018177.6	c.1831G>A	p.Asp611Asn	missense_variant	9/18	ENST00000261435.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
N4BP2	ENST00000261435.11	c.1831G>A	p.Asp611Asn	missense_variant	9/18	5	NM_018177.6	P1
N4BP2	ENST00000513269.1	c.772G>A	p.Asp258Asn	missense_variant	6/15	1
N4BP2	ENST00000511480.5	c.*1622G>A		3_prime_UTR_variant, NMD_transcript_variant	10/19	1
N4BP2	ENST00000706658.1	c.*1622G>A		3_prime_UTR_variant, NMD_transcript_variant	12/21

Frequencies

GnomAD3 genomes AF: 0.764 AC: 116107 AN: 151920 Hom.: 44729 Cov.: 32

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

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.: 18 AF XY: 0.778 AC XY: 479233 AN XY: 616012

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.: 32 AF XY: 0.770 AC XY: 57247 AN XY: 74304

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	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	13
Dann	Benign	0.29
DEOGEN2	Benign	0.00061	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	6.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.075
ClinPred		0.000021	T
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

Other links and lift over

dbSNP: rs794001; hg19: chr4-40121562; COSMIC: COSV54701351;