19-47036037-G-C

Position:

• chr19-47036037-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002517.4(NPAS1):​c.596G>C​(p.Gly199Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4027749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAS1	NM_002517.4	c.596G>C	p.Gly199Ala	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>C	p.Gly199Ala	missense_variant	6/12	1	NM_002517.4	ENSP00000469142.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453352 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000476 Hom.: 0

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

Apr 08, 2024

The c.596G>C (p.G199A) alteration is located in exon 5 (coding exon 5) of the NPAS1 gene. This alteration results from a G to C substitution at nucleotide position 596, causing the glycine (G) at amino acid position 199 to be replaced by an alanine (A). 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	0.24
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	.;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.9	.;.;D;D;.
REVEL	Benign	0.14
Sift	Benign	0.048	.;.;D;D;.
Sift4G	Benign	0.15	T;D;T;D;D
Polyphen		0.99	D;.;D;.;.
Vest4		0.67
MutPred		0.18		Loss of catalytic residue at L200 (P = 0.1139);.;Loss of catalytic residue at L200 (P = 0.1139);.;.;
MVP		0.43
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.56
gMVP		0.39

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: rs2056950898; hg19: chr19-47539295;