Genetic Variant NPIPB3:p.Glu174Lys (chr16-21404768-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_130464.3(NPIPB3):c.1168G>A(p.Glu390Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 6)

Exomes 𝑓: 0.00029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPIPB3
NM_130464.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.42

Variant links:

Genes affected

NPIPB3 (HGNC:28989): (nuclear pore complex interacting protein family member B3) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPB3 links:

ENSG00000290192 (HGNC:):

ENSG00000290192 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09147507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB3	NM_130464.3 link	c.1168G>A	p.Glu390Lys	missense_variant	Exon 8 of 12		NP_569731.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
NPIPB3	ENST00000542817.1 link	c.520G>A	p.Glu174Lys	missense_variant	Exon 1 of 2	5	ENSP00000444096.1	Q92617-4
ENSG00000290192	ENST00000703536.1 link	n.239+3574C>T		intron_variant	Intron 2 of 2
NPIPB3	ENST00000504841.6 link	c.*94G>A		downstream_gene_variant		1	ENSP00000446048.1	F5H4N5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

33940

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000146

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:

0.000159

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

54560

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

27370

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.00

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:

0.000339

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000285

AC:

333

AN:

1168282

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

169

AN XY:

593404

show subpopulations

Gnomad4 AFR exome

AF:

0.0000376

Gnomad4 AMR exome

AF:

0.0000478

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000390

Gnomad4 FIN exome

AF:

0.0000264

Gnomad4 NFE exome

AF:

0.000365

Gnomad4 OTH exome

AF:

0.000159

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000118

AC:

AN:

33940

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

17166

show subpopulations

Gnomad4 AFR

AF:

0.000146

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:

0.000159

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000743

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1168G>A (p.E390K) alteration is located in exon 8 (coding exon 7) of the NPIPB3 gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the glutamic acid (E) at amino acid position 390 to be replaced by a lysine (K). 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

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.6

DANN

Uncertain

1.0

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.75

M_CAP

Benign

0.0015

MetaRNN

Benign

0.091

MetaSVM

Benign

-1.1

PROVEAN

Benign

-1.4

REVEL

Benign

0.011

Sift

Benign

0.28

Sift4G

Benign

0.65

Vest4

0.12

MVP

0.043

ClinPred

0.064

gMVP

0.010

Splicing

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