19-47021166-C-G

Variant names:

• chr19-47021166-C-G
• rs756687294
• NM_002517.4:c.119C>G

Variant summary

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

The NM_002517.4(NPAS1):​c.119C>G​(p.Pro40Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,425,782 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. P40Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• 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]

ENSG00000307953 (HGNC:):

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=0.38856134).

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.119C>G	p.Pro40Arg	missense	Exon 2 of 12	NP_002508.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS1	ENST00000602212.6	TSL:1 MANE Select	c.119C>G	p.Pro40Arg	missense	Exon 2 of 12	ENSP00000469142.1	Q99742-1
	NPAS1	ENST00000449844.6	TSL:1	c.119C>G	p.Pro40Arg	missense	Exon 1 of 11	ENSP00000405290.1	Q99742-1
	NPAS1	ENST00000906441.1		c.119C>G	p.Pro40Arg	missense	Exon 2 of 12	ENSP00000576500.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1425782 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707302

African (AFR) AF: 0.00 AC: 0 AN: 31032

American (AMR) AF: 0.00 AC: 0 AN: 40596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24584

East Asian (EAS) AF: 0.00 AC: 0 AN: 36864

South Asian (SAS) AF: 0.00 AC: 0 AN: 81606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1096338

Other (OTH) AF: 0.00 AC: 0 AN: 58768

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.090
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.28		Gain of MoRF binding (P = 0.002)
MVP		0.23
MPC		1.3
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.051	Neutral
Varity_R		0.34
gMVP		0.50
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs756687294; hg19: chr19-47524423;