rs4974961

Positions:

• chr4-40095937-T-C

Variant summary

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

The NM_018177.6(N4BP2):​c.-114-1290T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 151,784 control chromosomes in the GnomAD database, including 10,079 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10079 hom., cov: 32)
• Consequence: N4BP2 NM_018177.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167

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 (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
N4BP2	NM_018177.6	c.-114-1290T>C		intron_variant		ENST00000261435.11	NP_060647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
N4BP2	ENST00000261435.11	c.-114-1290T>C		intron_variant		5	NM_018177.6	ENSP00000261435	P1
N4BP2	ENST00000511480.5	c.-114-1290T>C		intron_variant, NMD_transcript_variant		1		ENSP00000422436
N4BP2	ENST00000515550.1	c.-11-6138T>C		intron_variant		3		ENSP00000422057
N4BP2	ENST00000706658.1	c.-115+327T>C		intron_variant, NMD_transcript_variant				ENSP00000516486

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54300 AN: 151666 Hom.: 10084 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.519

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.377

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.358 AC: 54305 AN: 151784 Hom.: 10079 Cov.: 32 AF XY: 0.362 AC XY: 26840 AN XY: 74154

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.419

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.374

Alfa AF: 0.378 Hom.: 22509

Bravo AF: 0.347

Asia WGS AF: 0.465 AC: 1618 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.79

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: rs4974961; hg19: chr4-40097557;