NM_001164749.2:c.1438A>G

Variant names:

• chr14-33799745-A-G
• rs1163798900
• NM_001164749.2:c.1438A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164749.2(NPAS3):​c.1438A>G​(p.Asn480Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NPAS3 NM_001164749.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25572202).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS3	NM_001164749.2	MANE Select	c.1438A>G	p.Asn480Asp	missense	Exon 12 of 12	NP_001158221.1	X5D2Q4
	NPAS3	NM_173159.3		c.1399A>G	p.Asn467Asp	missense	Exon 12 of 12	NP_775182.1	Q8IXF0-3
	NPAS3	NM_001394988.1		c.1393A>G	p.Asn465Asp	missense	Exon 12 of 12	NP_001381917.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS3	ENST00000356141.9	TSL:1 MANE Select	c.1438A>G	p.Asn480Asp	missense	Exon 12 of 12	ENSP00000348460.4	Q8IXF0-1
	NPAS3	ENST00000357798.9	TSL:1	c.1399A>G	p.Asn467Asp	missense	Exon 12 of 12	ENSP00000350446.5	Q8IXF0-3
	NPAS3	ENST00000548645.5	TSL:1	c.1348A>G	p.Asn450Asp	missense	Exon 11 of 11	ENSP00000448916.1	Q8IXF0-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

African (AFR) AF: 0.0000242 AC: 1 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.46	N
PhyloP100		6.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.054
Sift	Benign	0.16	T
Sift4G	Benign	0.70	T
Polyphen		0.015	B
Vest4		0.23
MutPred		0.34		Loss of stability (P = 0.1347)
MVP		0.67
MPC		1.0
ClinPred		0.74	D
GERP RS		5.4
Varity_R		0.26
gMVP		0.40
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1163798900; hg19: chr14-34268951;