chr4-40119942-G-A

Variant names:

• chr4-40119942-G-A
• rs794001
• NM_018177.6:c.1831G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 0.76 (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
• Publications: 31 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=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	c.1831G>A	p.Asp611Asn	missense_variant	Exon 9 of 18	ENST00000261435.11	NP_060647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11	c.1831G>A	p.Asp611Asn	missense_variant	Exon 9 of 18	5	NM_018177.6	ENSP00000261435.6

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

GnomAD2 exomes AF: 0.810 AC: 158083 AN: 195264 AF XY: 0.813

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 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

African (AFR) AF: 0.671 AC: 18404 AN: 27444

American (AMR) AF: 0.874 AC: 26834 AN: 30714

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 15977 AN: 20756

East Asian (EAS) AF: 0.962 AC: 36882 AN: 38320

South Asian (SAS) AF: 0.927 AC: 63945 AN: 68944

European-Finnish (FIN) AF: 0.795 AC: 40382 AN: 50786

Middle Eastern (MID) AF: 0.764 AC: 3097 AN: 4054

European-Non Finnish (NFE) AF: 0.751 AC: 703389 AN: 936436

Other (OTH) AF: 0.781 AC: 40319 AN: 51614

GnomAD4 genome AF: 0.764 AC: 116192 AN: 152038 Hom.: 44756 Cov.: 32 AF XY: 0.770 AC XY: 57247 AN XY: 74304

African (AFR) AF: 0.685 AC: 28393 AN: 41448

American (AMR) AF: 0.823 AC: 12583 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2669 AN: 3468

East Asian (EAS) AF: 0.968 AC: 5025 AN: 5192

South Asian (SAS) AF: 0.931 AC: 4491 AN: 4822

European-Finnish (FIN) AF: 0.799 AC: 8425 AN: 10546

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.765 AC: 52004 AN: 67964

Other (OTH) AF: 0.774 AC: 1630 AN: 2106

Alfa AF: 0.773 Hom.: 136460

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
PhyloP100		0.91
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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