Genetic Variant NPIPB3:p.Gln30His (chr16-21405198-C-G) – 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.738G>C(p.Gln246His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 6)

Exomes 𝑓: 0.00019 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

NPIPB3
NM_130464.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.680

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=0.11233273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB3	NM_130464.3 link	c.738G>C	p.Gln246His	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.90G>C	p.Gln30His	missense_variant	Exon 1 of 2	5	ENSP00000444096.1	Q92617-4
NPIPB3	ENST00000504841.6 link	c.738G>C	p.Gln246His	missense_variant	Exon 7 of 7	1	ENSP00000446048.1	F5H4N5
NPIPB3	ENST00000419180.6 link	c.729G>C	p.Gln243His	missense_variant	Exon 9 of 9	3	ENSP00000413141.2	C9K082
ENSG00000290192	ENST00000703536.1 link	n.239+4004C>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

47882

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000736

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:

0.0000749

Gnomad OTH

AF:

0.00171

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000189

AC:

AN:

491550

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

AN XY:

258416

show subpopulations

Gnomad4 AFR exome

AF:

0.00411

Gnomad4 AMR exome

AF:

0.000357

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:

0.0000363

Gnomad4 OTH exome

AF:

0.000578

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000376

AC:

AN:

47920

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

21252

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000734

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000749

Gnomad4 OTH

AF:

0.00171

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.738G>C (p.Q246H) alteration is located in exon 8 (coding exon 7) of the NPIPB3 gene. This alteration results from a G to C substitution at nucleotide position 738, causing the glutamine (Q) at amino acid position 246 to be replaced by a histidine (H). 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

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.88

PROVEAN

Uncertain

-3.6

D;N;N

REVEL

Benign

0.060

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.037

D;D;.

Vest4

0.14

MVP

0.20

ClinPred

0.090

GERP RS

0.43

gMVP

0.024

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