rs12434716

Positions:

• chr14-33799961-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPAS3	NM_001164749.2	c.1654G>C	p.Ala552Pro	missense_variant	12/12	ENST00000356141.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPAS3	ENST00000356141.9	c.1654G>C	p.Ala552Pro	missense_variant	12/12	1	NM_001164749.2	A2

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

GnomAD3 exomes AF: 0.138 AC: 34484 AN: 250226 Hom.: 2799 AF XY: 0.133 AC XY: 18057 AN XY: 135524

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 SAS exome AF: 0.0746

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

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.0995

Gnomad4 EAS exome AF: 0.0192

Gnomad4 SAS exome AF: 0.0760

Gnomad4 FIN exome AF: 0.0783

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.145

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

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.0664

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.164

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 v4.3

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;.;.;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.099	T;T;T;T;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	.;.;.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.0	N;N;N;N;N;N
REVEL	Benign	0.015
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;B
Vest4		0.026, 0.093, 0.081, 0.042, 0.056
MPC		0.99
ClinPred		0.0035	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.53

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

Other links and lift over

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