Genetic Variant NPAS3:p.Val312Leu (chr14-33774418-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001164749.2(NPAS3):c.934G>C(p.Val312Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V312M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPAS3
NM_001164749.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.93

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein	UniProt
NPAS3	NM_001164749.2	MANE Select	c.934G>C	p.Val312Leu	missense	Exon 8 of 12	NP_001158221.1	X5D2Q4
NPAS3	NM_173159.3		c.895G>C	p.Val299Leu	missense	Exon 8 of 12	NP_775182.1	Q8IXF0-3
NPAS3	NM_001394988.1		c.889G>C	p.Val297Leu	missense	Exon 8 of 12	NP_001381917.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPAS3	ENST00000356141.9	TSL:1 MANE Select	c.934G>C	p.Val312Leu	missense	Exon 8 of 12	ENSP00000348460.4	Q8IXF0-1
NPAS3	ENST00000357798.9	TSL:1	c.895G>C	p.Val299Leu	missense	Exon 8 of 12	ENSP00000350446.5	Q8IXF0-3
NPAS3	ENST00000548645.5	TSL:1	c.844G>C	p.Val282Leu	missense	Exon 7 of 11	ENSP00000448916.1	Q8IXF0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

PhyloP100

9.9

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.33

Sift

Benign

0.031

Sift4G

Uncertain

0.0090

Polyphen

0.98

Vest4

0.66

MutPred

0.38

Loss of sheet (P = 0.0817)

MVP

0.32

MPC

1.7

ClinPred

0.98

GERP RS

5.8

Varity_R

0.52

gMVP

0.83

Mutation Taster

=57/43

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over