19-47036037-G-A

Position:

• chr19-47036037-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002517.4(NPAS1):​c.596G>A​(p.Gly199Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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]

NPAS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS1	NM_002517.4	c.596G>A	p.Gly199Glu	missense_variant	6/12	ENST00000602212.6	NP_002508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPAS1	ENST00000602212.6	c.596G>A	p.Gly199Glu	missense_variant	6/12	1	NM_002517.4	ENSP00000469142.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.596G>A (p.G199E) alteration is located in exon 5 (coding exon 5) of the NPAS1 gene. This alteration results from a G to A substitution at nucleotide position 596, causing the glycine (G) at amino acid position 199 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	.;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L;.;L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.8	.;.;D;D;.
REVEL	Benign	0.21
Sift	Benign	0.045	.;.;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.85
MutPred		0.21		Gain of loop (P = 0.1081);.;Gain of loop (P = 0.1081);.;.;
MVP		0.46
MPC		1.7
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.65
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-47539295;