chr19-47036007-G-A

Variant names:

• chr19-47036007-G-A
• rs201134548
• NM_002517.4:c.566G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002517.4(NPAS1):​c.566G>A​(p.Gly189Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000019 in 1,582,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. G189A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41
• Publications: 0 publications found

Genes affected

NPAS1 (HGNC:7894): (neuronal PAS domain protein 1) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. Studies of a related mouse gene suggest that it functions in neurons. The exact function of this gene is unclear, but it may play protective or modulatory roles during late embryogenesis and postnatal development. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3989232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002517.4. 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
	NPAS1	NM_002517.4	MANE Select	c.566G>A	p.Gly189Glu	missense	Exon 6 of 12	NP_002508.2
	NPAS1	NM_001321086.2		c.38G>A	p.Gly13Glu	missense	Exon 2 of 8	NP_001308015.1	Q99742-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS1	ENST00000602212.6	TSL:1 MANE Select	c.566G>A	p.Gly189Glu	missense	Exon 6 of 12	ENSP00000469142.1	Q99742-1
	NPAS1	ENST00000449844.6	TSL:1	c.566G>A	p.Gly189Glu	missense	Exon 5 of 11	ENSP00000405290.1	Q99742-1
	NPAS1	ENST00000906441.1		c.566G>A	p.Gly189Glu	missense	Exon 6 of 12	ENSP00000576500.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000464 AC: 1 AN: 215350 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429918 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710246

African (AFR) AF: 0.00 AC: 0 AN: 31988

American (AMR) AF: 0.00 AC: 0 AN: 38276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 82218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097970

Other (OTH) AF: 0.00 AC: 0 AN: 58896

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0050	N
PhyloP100		4.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.16
Sift	Benign	0.24	T
Sift4G	Benign	0.21	T
Polyphen		0.97	D
Vest4		0.61
MutPred		0.33		Gain of disorder (P = 0.1056)
MVP		0.37
MPC		1.8
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.33
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201134548; hg19: chr19-47539265;