Genetic Variant NPIPB5:p.Pro249Leu (chr16-22533729-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001395849.1(NPIPB5):c.746C>T(p.Pro249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 4)

Exomes 𝑓: 0.000059 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPIPB5
NM_001395849.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.673

Variant links:

Genes affected

NPIPB5 (HGNC:37233): (nuclear pore complex interacting protein family member B5) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPB5 links:

LOC105371131 (HGNC:):

LOC105371131 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3262322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB5	NM_001395849.1 link	c.746C>T	p.Pro249Leu	missense_variant	Exon 7 of 7	ENST00000424340.7	NP_001382778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPIPB5	ENST00000424340.7 link	c.746C>T	p.Pro249Leu	missense_variant	Exon 7 of 7	1	NM_001395849.1	ENSP00000440703.1		A8MRT5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

17616

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0143

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:

0.000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000590

AC:

AN:

440862

Hom.:

Cov.:

AF XY:

0.0000560

AC XY:

AN XY:

232076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000534

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:

0.0000950

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000114

AC:

AN:

17616

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

8218

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000149

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746C>T (p.P249L) alteration is located in exon 7 (coding exon 7) of the NPIPB5 gene. This alteration results from a C to T substitution at nucleotide position 746, causing the proline (P) at amino acid position 249 to be replaced by a leucine (L). 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

0.20

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;.;T;T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.0053

LIST_S2

Uncertain

0.88

.;D;D;.;D;.

M_CAP

Benign

0.0059

MetaRNN

Benign

0.33

T;T;T;T;T;T

MetaSVM

Benign

-0.79

PROVEAN

Pathogenic

-6.2

D;.;D;D;D;.

REVEL

Benign

0.077

Sift

Uncertain

0.0010

D;.;D;D;D;.

Sift4G

Uncertain

0.019

D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;.

Vest4

0.24, 0.25, 0.24, 0.30

MVP

0.45

ClinPred

0.96

Varity_R

0.16

gMVP

0.011

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

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