Variant 19-47039525-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4BS2

The NM_002517.4(NPAS1):c.923G>A(p.Arg308His) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,604,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

NPAS1
NM_002517.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

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:

NPAS1 (HGNC:):

NPAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, FATHMM_MKL, M_CAP, PrimateAI, PROVEAN [when AlphaMissense, BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.29307914).

BS2

High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS1	NM_002517.4 linkuse as main transcript	c.923G>A	p.Arg308His	missense_variant	8/12	ENST00000602212.6	NP_002508.2	Q99742-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPAS1	ENST00000602212.6 linkuse as main transcript	c.923G>A	p.Arg308His	missense_variant	8/12	1	NM_002517.4	ENSP00000469142.1		Q99742-1

Frequencies

GnomAD3 genomes

AF:

0.000696

AC:

106

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000483

AC:

118

AN:

244112

Hom.:

AF XY:

0.000484

AC XY:

AN XY:

132200

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000624

Gnomad ASJ exome

AF:

0.000532

Gnomad EAS exome

AF:

0.0000552

Gnomad SAS exome

AF:

0.0000338

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.000745

Gnomad OTH exome

AF:

0.000679

GnomAD4 exome

AF:

0.000675

AC:

980

AN:

1452164

Hom.:

Cov.:

AF XY:

0.000677

AC XY:

488

AN XY:

721194

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000525

Gnomad4 ASJ exome

AF:

0.000703

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000809

Gnomad4 OTH exome

AF:

0.000467

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152336

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000807

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000486

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.923G>A (p.R308H) alteration is located in exon 7 (coding exon 7) of the NPAS1 gene. This alteration results from a G to A substitution at nucleotide position 923, causing the arginine (R) at amino acid position 308 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;.;T;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

M;.;M;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.7

.;.;D;D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.82

MVP

0.57

MPC

1.6

ClinPred

0.17

GERP RS

4.8

Varity_R

0.75

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over