19-47039474-C-A

Variant names:

• chr19-47039474-C-A
• rs2056995557
• NM_002517.4:c.872C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002517.4(NPAS1):​c.872C>A​(p.Pro291His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

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.872C>A	p.Pro291His	missense	Exon 8 of 12	NP_002508.2
	NPAS1	NM_001321086.2		c.344C>A	p.Pro115His	missense	Exon 4 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.872C>A	p.Pro291His	missense	Exon 8 of 12	ENSP00000469142.1	Q99742-1
	NPAS1	ENST00000449844.6	TSL:1	c.872C>A	p.Pro291His	missense	Exon 7 of 11	ENSP00000405290.1	Q99742-1
	NPAS1	ENST00000906441.1		c.872C>A	p.Pro291His	missense	Exon 8 of 12	ENSP00000576500.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.4	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.64		Loss of glycosylation at P291 (P = 0.0294)
MVP		0.44
MPC		1.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.87
gMVP		0.60
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs2056995557; hg19: chr19-47542732;