rs144841798

Variant names:

• chr14-33797565-C-A
• rs144841798
• NM_001164749.2:c.1410C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-33797565-C-A
• chr14-33797565-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001164749.2(NPAS3):​c.1410C>A​(p.Asp470Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,613,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: NPAS3 NM_001164749.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037963867).
• BS2: High AC in GnomAd4 at 49 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS3	NM_001164749.2	MANE Select	c.1410C>A	p.Asp470Glu	missense	Exon 11 of 12	NP_001158221.1	X5D2Q4
	NPAS3	NM_173159.3		c.1371C>A	p.Asp457Glu	missense	Exon 11 of 12	NP_775182.1	Q8IXF0-3
	NPAS3	NM_001394988.1		c.1365C>A	p.Asp455Glu	missense	Exon 11 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.1410C>A	p.Asp470Glu	missense	Exon 11 of 12	ENSP00000348460.4	Q8IXF0-1
	NPAS3	ENST00000357798.9	TSL:1	c.1371C>A	p.Asp457Glu	missense	Exon 11 of 12	ENSP00000350446.5	Q8IXF0-3
	NPAS3	ENST00000548645.5	TSL:1	c.1320C>A	p.Asp440Glu	missense	Exon 10 of 11	ENSP00000448916.1	Q8IXF0-2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251460 AF XY: 0.000368

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000738

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000555 AC: 811 AN: 1461770 Hom.: 1 Cov.: 31 AF XY: 0.000516 AC XY: 375 AN XY: 727198

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000685 AC: 762 AN: 1111908

Other (OTH) AF: 0.000348 AC: 21 AN: 60390

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74348

African (AFR) AF: 0.0000965 AC: 4 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000504 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

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	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.091
Sift	Benign	0.19	T
Sift4G	Benign	0.48	T
Polyphen		0.0060	B
Vest4		0.20
MutPred		0.21		Gain of methylation at K469 (P = 0.0905)
MVP		0.24
MPC		1.7
ClinPred		0.085	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.36
Mutation Taster		=88/12	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: rs144841798; hg19: chr14-34266771;