Genetic Variant NPIPB5:p.Thr322Lys (chr16-22533948-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001395849.1(NPIPB5):c.965C>A(p.Thr322Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000018 ( 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: 0.904

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04188156).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395849.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPIPB5	NM_001395849.1	MANE Select	c.965C>A	p.Thr322Lys	missense	Exon 7 of 7	NP_001382778.1	A8MRT5
NPIPB5	NM_001135865.3		c.965C>A	p.Thr322Lys	missense	Exon 9 of 9	NP_001129337.1	A8MRT5
NPIPB5	NM_001395850.1		c.965C>A	p.Thr322Lys	missense	Exon 8 of 8	NP_001382779.1	A8MRT5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPIPB5	ENST00000424340.7	TSL:1 MANE Select	c.965C>A	p.Thr322Lys	missense	Exon 7 of 7	ENSP00000440703.1	A8MRT5
NPIPB5	ENST00000528249.5	TSL:1	c.965C>A	p.Thr322Lys	missense	Exon 7 of 7	ENSP00000431553.1	E9PKP1
NPIPB5	ENST00000517539.6	TSL:5	c.965C>A	p.Thr322Lys	missense	Exon 8 of 8	ENSP00000430633.1	A8MRT5

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

73414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000295

AC:

AN:

54226

AF XY:

0.000220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000525

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000178

AC:

AN:

1012484

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

520190

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27686

American (AMR)

AF:

0.000438

AC:

AN:

41060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23020

East Asian (EAS)

AF:

0.00

AC:

AN:

36708

South Asian (SAS)

AF:

0.00

AC:

AN:

78540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3470

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

717932

Other (OTH)

AF:

0.00

AC:

AN:

46264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000039479), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000136

AC:

AN:

73414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35902

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22820

American (AMR)

AF:

0.000134

AC:

AN:

7450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1798

East Asian (EAS)

AF:

0.00

AC:

AN:

1724

South Asian (SAS)

AF:

0.00

AC:

AN:

1948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

31360

Other (OTH)

AF:

0.00

AC:

AN:

968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.035

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.80

M_CAP

Benign

0.0020

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

PhyloP100

0.90

PROVEAN

Benign

-0.95

REVEL

Benign

0.035

Sift

Benign

0.078

Sift4G

Benign

0.17

Polyphen

0.99

Vest4

0.13

MutPred

0.34

Gain of ubiquitination at T322 (P = 0.0066)

MVP

0.067

ClinPred

0.061

Varity_R

0.14

gMVP

0.0099

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over