Genetic Variant NPAS3:c.559-9G>A (chr14-33676202-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001164749.2(NPAS3):c.559-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000503 in 1,612,792 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

NPAS3
NM_001164749.2 intron

Scores

Splicing: ADA: 0.00002439

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.17

Publications

0 publications found

Variant links:

Genes affected

NPAS3 (HGNC:19311): (neuronal PAS domain protein 3) This gene encodes a member of the basic helix-loop-helix and PAS domain-containing family of transcription factors. The encoded protein is localized to the nucleus and may regulate genes involved in neurogenesis. Chromosomal abnormalities that affect the coding potential of this gene are associated with schizophrenia and cognitive disability. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

NPAS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 14-33676202-G-A is Benign according to our data. Variant chr14-33676202-G-A is described in ClinVar as Benign. ClinVar VariationId is 721504.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 397 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164749.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPAS3	NM_001164749.2	MANE Select	c.559-9G>A	intron	N/A	NP_001158221.1	X5D2Q4
NPAS3	NM_173159.3		c.520-9G>A	intron	N/A	NP_775182.1	Q8IXF0-3
NPAS3	NM_001394988.1		c.514-9G>A	intron	N/A	NP_001381917.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NPAS3	ENST00000356141.9	TSL:1 MANE Select	c.559-9G>A	intron	N/A	ENSP00000348460.4	Q8IXF0-1
NPAS3	ENST00000357798.9	TSL:1	c.520-9G>A	intron	N/A	ENSP00000350446.5	Q8IXF0-3
NPAS3	ENST00000548645.5	TSL:1	c.469-9G>A	intron	N/A	ENSP00000448916.1	Q8IXF0-2

Frequencies

GnomAD3 genomes

AF:

0.00262

AC:

398

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00889

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000103

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000736

AC:

184

AN:

249916

AF XY:

0.000577

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.000552

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000284

AC:

415

AN:

1460600

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

161

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.00815

AC:

272

AN:

33354

American (AMR)

AF:

0.000673

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

1111364

Other (OTH)

AF:

0.000613

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00261

AC:

397

AN:

152192

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00883

AC:

367

AN:

41540

American (AMR)

AF:

0.00144

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68004

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.00124

Hom.:

Bravo

AF:

0.00293

EpiCase

AF:

0.000109

EpiControl

AF:

0.000238

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0060

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