15-24676003-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_018958.3(NPAP1):c.136C>T(p.Pro46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,600,666 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 47 hom. )

Consequence

NPAP1
NM_018958.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0330

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058502555).

BP6

Variant 15-24676003-C-T is Benign according to our data. Variant chr15-24676003-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 789222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 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.136C>T	p.Pro46Ser	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.136C>T	p.Pro46Ser	missense	Exon 1 of 1	ENSP00000333735.3	Q9NZP6
ENSG00000286110	ENST00000650707.1		n.407+105875C>T		intron	N/A
ENSG00000286110	ENST00000651136.1		n.1530+51898C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

737

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00398

AC:

899

AN:

226022

AF XY:

0.00390

show subpopulations

Gnomad AFR exome

AF:

0.00120

Gnomad AMR exome

AF:

0.00170

Gnomad ASJ exome

AF:

0.000552

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00260

Gnomad NFE exome

AF:

0.00726

Gnomad OTH exome

AF:

0.00518

GnomAD4 exome

AF:

0.00746

AC:

10800

AN:

1448366

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

5110

AN XY:

720572

show subpopulations

African (AFR)

AF:

0.000684

AC:

AN:

32148

American (AMR)

AF:

0.00208

AC:

AN:

43174

Ashkenazi Jewish (ASJ)

AF:

0.00114

AC:

AN:

25462

East Asian (EAS)

AF:

0.00

AC:

AN:

38388

South Asian (SAS)

AF:

0.000599

AC:

AN:

85176

European-Finnish (FIN)

AF:

0.00227

AC:

118

AN:

51882

Middle Eastern (MID)

AF:

0.000532

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00906

AC:

10029

AN:

1106772

Other (OTH)

AF:

0.00767

AC:

458

AN:

59724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

617

1234

1850

2467

3084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.00484

AC:

737

AN:

152300

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41570

American (AMR)

AF:

0.00176

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00869

AC:

591

AN:

68010

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00632

Hom.:

Bravo

AF:

0.00453

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00186

AC:

ESP6500EA

AF:

0.00705

AC:

ExAC

AF:

0.00374

AC:

449

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.37

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.033

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.040

Sift

Benign

0.038

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.16

MVP

0.072

MPC

0.32

ClinPred

0.027

GERP RS

1.3

PromoterAI

-0.0043

Neutral

(source)

Varity_R

0.086

gMVP

0.28

Mutation Taster

=100/0

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