rs12434716

Variant names:

• chr14-33799961-G-C
• rs12434716
• NM_001164749.2:c.1654G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001164749.2(NPAS3):​c.1654G>C​(p.Ala552Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,880 control chromosomes in the GnomAD database, including 20,956 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2119 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18837 hom.)
• Consequence: NPAS3 NM_001164749.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 26 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011625588).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

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.1654G>C	p.Ala552Pro	missense	Exon 12 of 12	NP_001158221.1	X5D2Q4
	NPAS3	NM_173159.3		c.1615G>C	p.Ala539Pro	missense	Exon 12 of 12	NP_775182.1	Q8IXF0-3
	NPAS3	NM_001394988.1		c.1609G>C	p.Ala537Pro	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.1654G>C	p.Ala552Pro	missense	Exon 12 of 12	ENSP00000348460.4	Q8IXF0-1
	NPAS3	ENST00000357798.9	TSL:1	c.1615G>C	p.Ala539Pro	missense	Exon 12 of 12	ENSP00000350446.5	Q8IXF0-3
	NPAS3	ENST00000548645.5	TSL:1	c.1564G>C	p.Ala522Pro	missense	Exon 11 of 11	ENSP00000448916.1	Q8IXF0-2

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24147 AN: 152158 Hom.: 2115 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0724

Gnomad FIN AF: 0.0664

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.138 AC: 34484 AN: 250226 AF XY: 0.133

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0757

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.155 AC: 226648 AN: 1461604 Hom.: 18837 Cov.: 37 AF XY: 0.152 AC XY: 110746 AN XY: 727126

African (AFR) AF: 0.197 AC: 6594 AN: 33480

American (AMR) AF: 0.193 AC: 8616 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0995 AC: 2599 AN: 26130

East Asian (EAS) AF: 0.0192 AC: 763 AN: 39700

South Asian (SAS) AF: 0.0760 AC: 6554 AN: 86258

European-Finnish (FIN) AF: 0.0783 AC: 4169 AN: 53212

Middle Eastern (MID) AF: 0.111 AC: 639 AN: 5768

European-Non Finnish (NFE) AF: 0.169 AC: 187938 AN: 1111962

Other (OTH) AF: 0.145 AC: 8776 AN: 60386

GnomAD4 genome AF: 0.159 AC: 24174 AN: 152276 Hom.: 2119 Cov.: 33 AF XY: 0.153 AC XY: 11388 AN XY: 74430

African (AFR) AF: 0.194 AC: 8073 AN: 41556

American (AMR) AF: 0.176 AC: 2686 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3470

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5170

South Asian (SAS) AF: 0.0714 AC: 345 AN: 4830

European-Finnish (FIN) AF: 0.0664 AC: 705 AN: 10618

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11343 AN: 68014

Other (OTH) AF: 0.164 AC: 345 AN: 2110

Alfa AF: 0.158 Hom.: 1574

Bravo AF: 0.169

TwinsUK AF: 0.157 AC: 583

ALSPAC AF: 0.163 AC: 629

ESP6500AA AF: 0.196 AC: 863

ESP6500EA AF: 0.159 AC: 1368

ExAC AF: 0.141 AC: 17063

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.099	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.99
ClinPred		0.0035	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.53
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12434716; hg19: chr14-34269167; COSMIC: COSV60821347;