4-40102431-A-G

Position:

• chr4-40102431-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018177.6(N4BP2):​c.586A>G​(p.Met196Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,612,076 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.029 (226 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (206 hom.)
• Consequence: N4BP2 NM_018177.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.562

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015435815).
• BP6: Variant 4-40102431-A-G is Benign according to our data. Variant chr4-40102431-A-G is described in ClinVar as [Benign]. Clinvar id is 791976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
N4BP2	NM_018177.6	c.586A>G	p.Met196Val	missense_variant	4/18	ENST00000261435.11	NP_060647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11	c.586A>G	p.Met196Val	missense_variant	4/18	5	NM_018177.6	ENSP00000261435	P1
N4BP2	ENST00000511480.5	c.*377A>G		3_prime_UTR_variant, NMD_transcript_variant	5/19	1		ENSP00000422436
N4BP2	ENST00000515550.1	c.346A>G	p.Met116Val	missense_variant	3/3	3		ENSP00000422057
N4BP2	ENST00000706658.1	c.*377A>G		3_prime_UTR_variant, NMD_transcript_variant	7/21			ENSP00000516486

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4352 AN: 152166 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00766 AC: 1901 AN: 248236 Hom.: 96 AF XY: 0.00594 AC XY: 800 AN XY: 134656

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00482

GnomAD4 exome AF: 0.00303 AC: 4430 AN: 1459792 Hom.: 206 Cov.: 33 AF XY: 0.00268 AC XY: 1949 AN XY: 726220

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00540

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.0287 AC: 4372 AN: 152284 Hom.: 226 Cov.: 32 AF XY: 0.0280 AC XY: 2084 AN XY: 74478

Gnomad4 AFR AF: 0.0991

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00386 Hom.: 35

Bravo AF: 0.0329

ESP6500AA AF: 0.0915 AC: 402

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00949 AC: 1152

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.45
DANN	Benign	0.32
DEOGEN2	Benign	0.0014	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.20
Sift	Benign	0.30	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.045
MVP		0.44
MPC		0.078
ClinPred		0.0074	T
GERP RS		1.5
Varity_R		0.073
gMVP		0.17

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: rs10014170; hg19: chr4-40104051;