19-47021168-T-C

Variant names:

• chr19-47021168-T-C
• rs2056837804
• NM_002517.4:c.121T>C

Variant summary

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

The NM_002517.4(NPAS1):​c.121T>C​(p.Cys41Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NPAS1 NM_002517.4 missense, splice_region
• Scores: Splicing: ADA: 0.01008
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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

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=0.27232012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS1	NM_002517.4	c.121T>C	p.Cys41Arg	missense_variant, splice_region_variant	Exon 2 of 12	ENST00000602212.6	NP_002508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS1	ENST00000602212.6	c.121T>C	p.Cys41Arg	missense_variant, splice_region_variant	Exon 2 of 12	1	NM_002517.4	ENSP00000469142.1
NPAS1	ENST00000449844.6	c.121T>C	p.Cys41Arg	missense_variant, splice_region_variant	Exon 1 of 11	1		ENSP00000405290.1
NPAS1	ENST00000602189.5	c.-171+1171T>C		intron_variant	Intron 1 of 9	5		ENSP00000472679.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423868 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 706214

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: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121T>C (p.C41R) alteration is located in exon 1 (coding exon 1) of the NPAS1 gene. This alteration results from a T to C substitution at nucleotide position 121, causing the cysteine (C) at amino acid position 41 to be replaced by an arginine (R). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Benign	0.74
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.42	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	.;N
REVEL	Benign	0.24
Sift	Benign	0.34	.;T
Sift4G	Benign	0.72	T;T
Polyphen		0.014	B;B
Vest4		0.68
MutPred		0.26		Gain of MoRF binding (P = 0.0093);Gain of MoRF binding (P = 0.0093);
MVP		0.21
MPC		1.4
ClinPred		0.35	T
GERP RS		3.9
Varity_R		0.71
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.15
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: rs2056837804; hg19: chr19-47524425;