Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001277325.2(NPIPA5):c.962C>T(p.Pro321Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,416,716 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.000095 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000047 ( 3 hom. )

Consequence

NPIPA5
NM_001277325.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.00

Publications

1 publications found

Variant links:

Genes affected

NPIPA5 (HGNC:41980): (nuclear pore complex interacting protein family member A5) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13800871).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277325.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPIPA5	NM_001277325.2	MANE Select	c.962C>T	p.Pro321Leu	missense	Exon 8 of 8	NP_001264254.1
	NPIPA5	NM_001351200.1		c.*333C>T		3_prime_UTR	Exon 9 of 9	NP_001338129.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPIPA5	ENST00000360151.9	TSL:1 MANE Select	c.962C>T	p.Pro321Leu	missense	Exon 8 of 8	ENSP00000433597.1

Frequencies

GnomAD3 genomes

AF:

0.0000953

AC:

AN:

125868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000272

Gnomad FIN

AF:

0.000264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000481

AC:

AN:

207992

AF XY:

0.0000611

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000396

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1290758

Hom.:

Cov.:

AF XY:

0.0000515

AC XY:

AN XY:

641274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30546

American (AMR)

AF:

0.000231

AC:

AN:

34668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21466

East Asian (EAS)

AF:

0.000899

AC:

AN:

25596

South Asian (SAS)

AF:

0.0000768

AC:

AN:

78168

European-Finnish (FIN)

AF:

0.0000305

AC:

AN:

32736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3544

European-Non Finnish (NFE)

AF:

0.0000217

AC:

AN:

1012840

Other (OTH)

AF:

0.0000195

AC:

AN:

51194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000953

AC:

AN:

125958

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

60608

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:

35324

American (AMR)

AF:

0.00

AC:

AN:

11534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3002

East Asian (EAS)

AF:

0.00

AC:

AN:

2550

South Asian (SAS)

AF:

0.000273

AC:

AN:

3666

European-Finnish (FIN)

AF:

0.000264

AC:

AN:

7582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

59444

Other (OTH)

AF:

0.00

AC:

AN:

1746

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000266454), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.317

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000849

Hom.:

ExAC

AF:

0.00000869

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Oromandibular-limb hypogenesis spectrum (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.023

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.50

M_CAP

Benign

0.018

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.3

PhyloP100

0.0

PROVEAN

Benign

-2.1

REVEL

Benign

0.089

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Vest4

0.097

MutPred

0.50

Loss of glycosylation at P321 (P = 0.0143)

MVP

0.043

MPC

2.0

ClinPred

0.14

Varity_R

0.076

gMVP

0.010

Mutation Taster

=99/1

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.

rs886037884

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over