chr19-47036108-C-T

Variant names:

• chr19-47036108-C-T
• rs1216037930
• NM_002517.4:c.667C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002517.4(NPAS1):​c.667C>T​(p.Leu223Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,417,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06826025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS1	NM_002517.4	c.667C>T	p.Leu223Phe	missense_variant	Exon 6 of 12	ENST00000602212.6	NP_002508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS1	ENST00000602212.6	c.667C>T	p.Leu223Phe	missense_variant	Exon 6 of 12	1	NM_002517.4	ENSP00000469142.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417120 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700836

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667C>T (p.L223F) alteration is located in exon 5 (coding exon 5) of the NPAS1 gene. This alteration results from a C to T substitution at nucleotide position 667, causing the leucine (L) at amino acid position 223 to be replaced by a phenylalanine (F). 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	0.090
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;.;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.068	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;L;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.93	.;.;N;N;.
REVEL	Benign	0.027
Sift	Benign	0.58	.;.;T;T;.
Sift4G	Benign	0.70	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.
Vest4		0.25
MutPred		0.24		Gain of glycosylation at S220 (P = 0.0704);.;Gain of glycosylation at S220 (P = 0.0704);.;.;
MVP		0.38
MPC		0.64
ClinPred		0.22	T
GERP RS		2.7
Varity_R		0.053
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1216037930; hg19: chr19-47539366;