15-24675947-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018958.3(NPAP1):c.80C>G(p.Pro27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,590,462 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

NPAP1
NM_018958.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.533

Publications

0 publications found

Variant links:

Genes affected

NPAP1 (HGNC:1190): (nuclear pore associated protein 1) This intronless retrogene is located in the Prader-Willi syndrome region on chromosome 15. This gene exhibits tissue-specific imprinting. Expression in adult testis and brain is biallelic, while expression in fetal brain is monoallelic and only from the paternal chromosome. The encoded protein is associated with the nuclear pore complex. [provided by RefSeq, Mar 2021]

NPAP1 links:

ENSG00000286110 (HGNC:):

ENSG00000286110 links:

PWRN1 (HGNC:33235): (Prader-Willi region non-protein coding RNA 1) This gene is located in the Prader-Willi syndrome (PWS) region of chromosome 15, which is known to undergo imprinting. The transcript is believed to be non-coding. It is bi-allelically expressed in testis and kidney, but mono-allelically expressed from the paternal allele in brain. This gene is poly-adenylated and is known to undergo alternative splicing. Transcript variants may represent part of a complex imprinting center-SNURF-SNRPN transcription unit. The contribution of this gene to the PWS phenotype is unknown, but it has been suggested that it may play a role in establishing paternal imprinting in the PWS region, perhaps by maintaining the paternal allele in an open chromatin configuration. [provided by RefSeq, Sep 2009]

PWRN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005283475).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018958.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAP1	NM_018958.3	MANE Select	c.80C>G	p.Pro27Arg	missense	Exon 1 of 1	NP_061831.2	Q9NZP6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPAP1	ENST00000329468.5	TSL:6 MANE Select	c.80C>G	p.Pro27Arg	missense	Exon 1 of 1	ENSP00000333735.3	Q9NZP6
ENSG00000286110	ENST00000650707.1		n.407+105819C>G		intron	N/A
ENSG00000286110	ENST00000651136.1		n.1530+51842C>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.0000588

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000650

AC:

137

AN:

210912

AF XY:

0.000502

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.000455

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.000600

GnomAD4 exome

AF:

0.000334

AC:

480

AN:

1438186

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

219

AN XY:

714998

show subpopulations

African (AFR)

AF:

0.0125

AC:

391

AN:

31396

American (AMR)

AF:

0.000531

AC:

AN:

41444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24846

East Asian (EAS)

AF:

0.00

AC:

AN:

38116

South Asian (SAS)

AF:

0.0000831

AC:

AN:

84186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51286

Middle Eastern (MID)

AF:

0.000377

AC:

AN:

5302

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1102512

Other (OTH)

AF:

0.000880

AC:

AN:

59098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00340

AC:

517

AN:

152276

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

235

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0120

AC:

499

AN:

41584

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

108

135

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:

0.000195

Hom.:

Bravo

AF:

0.00380

ESP6500AA

AF:

0.00766

AC:

ESP6500EA

AF:

0.000132

AC:

ExAC

AF:

0.000881

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0064

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

-0.53

PrimateAI

Benign

0.45

PROVEAN

Benign

0.030

REVEL

Benign

0.064

Sift

Benign

0.26

Sift4G

Pathogenic

0.0

Polyphen

0.96

Vest4

0.13

MVP

0.040

MPC

0.37

ClinPred

0.021

GERP RS

-4.8

PromoterAI

0.063

Neutral

(source)

Varity_R

0.036

gMVP

0.43

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over