11-66423199-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_178864.4(NPAS4):​c.775C>G​(p.Leu259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NPAS4
NM_178864.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54
Variant links:
Genes affected
NPAS4 (HGNC:18983): (neuronal PAS domain protein 4) NXF is a member of the basic helix-loop-helix-PER (MIM 602260)-ARNT (MIM 126110)-SIM (see SIM2; MIM 600892) (bHLH-PAS) class of transcriptional regulators, which are involved in a wide range of physiologic and developmental events (Ooe et al., 2004 [PubMed 14701734]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.389659).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPAS4NM_178864.4 linkc.775C>G p.Leu259Val missense_variant Exon 5 of 8 ENST00000311034.7 NP_849195.2 Q8IUM7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPAS4ENST00000311034.7 linkc.775C>G p.Leu259Val missense_variant Exon 5 of 8 1 NM_178864.4 ENSP00000311196.2 Q8IUM7-1
NPAS4ENST00000525148.1 linkn.698+258C>G intron_variant Intron 4 of 6 1 ENSP00000433135.1 Q8IUM7-3
NPAS4ENST00000524617.1 linkn.58+258C>G intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457476
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
724510
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.775C>G (p.L259V) alteration is located in exon 5 (coding exon 5) of the NPAS4 gene. This alteration results from a C to G substitution at nucleotide position 775, causing the leucine (L) at amino acid position 259 to be replaced by a valine (V). 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
0.24
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.39
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.98
L
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.19
Sift
Benign
0.093
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.96
D
Vest4
0.29
MutPred
0.52
Loss of helix (P = 0.0376);
MVP
0.36
MPC
0.53
ClinPred
0.83
D
GERP RS
4.7
Varity_R
0.17
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs751381904; hg19: chr11-66190670; API