Variant 19-47021156-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002517.4(NPAS1):c.109C>G(p.Pro37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000932 in 1,588,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

NPAS1
NM_002517.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009855986).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS1	NM_002517.4 linkuse as main transcript	c.109C>G	p.Pro37Ala	missense_variant	2/12	ENST00000602212.6	NP_002508.2	Q99742-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPAS1	ENST00000602212.6 linkuse as main transcript	c.109C>G	p.Pro37Ala	missense_variant	2/12	1	NM_002517.4	ENSP00000469142.1	Q99742-1
NPAS1	ENST00000449844.6 linkuse as main transcript	c.109C>G	p.Pro37Ala	missense_variant	1/11	1		ENSP00000405290.1	Q99742-1
NPAS1	ENST00000602189.5 linkuse as main transcript	c.-171+1159C>G		intron_variant		5		ENSP00000472679.1	M0R2M8

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00462

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000186

AC:

AN:

204366

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

112848

show subpopulations

Gnomad AFR exome

AF:

0.0000920

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.000410

GnomAD4 exome

AF:

0.0000877

AC:

126

AN:

1436610

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

713406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00334

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000209

Gnomad4 OTH exome

AF:

0.000321

GnomAD4 genome

AF:

0.000145

AC:

AN:

151578

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

74016

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00462

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000885

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000409

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000108

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

May 04, 2022

The c.109C>G (p.P37A) alteration is located in exon 1 (coding exon 1) of the NPAS1 gene. This alteration results from a C to G substitution at nucleotide position 109, causing the proline (P) at amino acid position 37 to be replaced by an alanine (A). 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

0.059

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.50

.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0099

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.97

L;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.12

Sift

Uncertain

0.025

.;D

Sift4G

Uncertain

0.030

D;D

Polyphen

0.91

P;P

Vest4

0.28

MutPred

0.19

Gain of MoRF binding (P = 0.0514);Gain of MoRF binding (P = 0.0514);

MVP

0.16

MPC

0.57

ClinPred

0.039

GERP RS

-1.1

Varity_R

0.054

gMVP

0.43

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