19-47036108-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
NPAS1NM_002517.4 linkc.667C>T p.Leu223Phe missense_variant Exon 6 of 12 ENST00000602212.6 NP_002508.2 Q99742-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPAS1ENST00000602212.6 linkc.667C>T p.Leu223Phe missense_variant Exon 6 of 12 1 NM_002517.4 ENSP00000469142.1 Q99742-1

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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1216037930; hg19: chr19-47539366; API