Genetic Variant NPAS1:p.Pro40Gln (chr19-47021166-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002517.4(NPAS1):c.119C>A(p.Pro40Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,577,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NPAS1
NM_002517.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

Publications

0 publications found

Variant links:

Genes affected

NPAS1 (HGNC:7894): (neuronal PAS domain protein 1) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. Studies of a related mouse gene suggest that it functions in neurons. The exact function of this gene is unclear, but it may play protective or modulatory roles during late embryogenesis and postnatal development. [provided by RefSeq, Jul 2008]

NPAS1 links:

ENSG00000307953 (HGNC:):

ENSG00000307953 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25060236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002517.4. 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
	NPAS1	NM_002517.4	MANE Select	c.119C>A	p.Pro40Gln	missense	Exon 2 of 12	NP_002508.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPAS1	ENST00000602212.6	TSL:1 MANE Select	c.119C>A	p.Pro40Gln	missense	Exon 2 of 12	ENSP00000469142.1	Q99742-1
NPAS1	ENST00000449844.6	TSL:1	c.119C>A	p.Pro40Gln	missense	Exon 1 of 11	ENSP00000405290.1	Q99742-1
NPAS1	ENST00000906441.1		c.119C>A	p.Pro40Gln	missense	Exon 2 of 12	ENSP00000576500.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151626

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:

0.000588

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:

0.0000261

AC:

AN:

191600

AF XY:

0.0000189

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1425782

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31032

American (AMR)

AF:

0.00

AC:

AN:

40596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24584

East Asian (EAS)

AF:

0.0000814

AC:

AN:

36864

South Asian (SAS)

AF:

0.00

AC:

AN:

81606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5338

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096338

Other (OTH)

AF:

0.00

AC:

AN:

58768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.658

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

AF:

0.0000198

AC:

AN:

151626

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41272

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000588

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67858

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000250

AC:

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

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.2

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.7

REVEL

Benign

0.12

Sift

Uncertain

0.021

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.51

MutPred

0.23

Loss of glycosylation at P40 (P = 0.0493)

MVP

0.24

MPC

1.2

ClinPred

0.43

GERP RS

3.9

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.24

gMVP

0.42

Mutation Taster

=90/10

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

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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