Genetic Variant N4BP1:p.Leu567Val (chr16-48560944-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153029.4(N4BP1):c.1699C>G(p.Leu567Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

N4BP1
NM_153029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Variant links:

Genes affected

N4BP1 (HGNC:29850): (NEDD4 binding protein 1) Enables mRNA binding activity; ribonuclease activity; and ubiquitin binding activity. Involved in cellular response to UV and negative regulation of viral genome replication. Predicted to be located in cytosol and nucleolus. Predicted to be active in PML body. [provided by Alliance of Genome Resources, Apr 2022]

N4BP1 links:

ENSG00000261267 (HGNC:):

ENSG00000261267 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06762132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
N4BP1	NM_153029.4 link	c.1699C>G	p.Leu567Val	missense_variant	Exon 2 of 7	ENST00000262384.4	NP_694574.3	O75113
N4BP1	XM_011523482.2 link	c.1699C>G	p.Leu567Val	missense_variant	Exon 2 of 6		XP_011521784.1
N4BP1	XR_007064930.1 link	n.1907C>G		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
N4BP1	ENST00000262384.4 link	c.1699C>G	p.Leu567Val	missense_variant	Exon 2 of 7	1	NM_153029.4	ENSP00000262384.3	O75113
N4BP1	ENST00000564124.5 link	n.1801C>G		non_coding_transcript_exon_variant	Exon 2 of 6	5
ENSG00000261267	ENST00000563994.1 link	n.173+278G>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248892

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000258

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1699C>G (p.L567V) alteration is located in exon 2 (coding exon 2) of the N4BP1 gene. This alteration results from a C to G substitution at nucleotide position 1699, causing the leucine (L) at amino acid position 567 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.018

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.68

M_CAP

Benign

0.0095

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.11

REVEL

Benign

0.13

Sift

Benign

0.95

Sift4G

Benign

0.81

Polyphen

0.094

Vest4

0.10

MVP

0.42

MPC

0.13

ClinPred

0.032

GERP RS

6.0

Varity_R

0.047

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over