11-66422776-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178864.4(NPAS4):​c.533C>T​(p.Pro178Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P178H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPAS4
NM_178864.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.199875).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPAS4NM_178864.4 linkc.533C>T p.Pro178Leu missense_variant Exon 4 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.533C>T p.Pro178Leu missense_variant Exon 4 of 8 1 NM_178864.4 ENSP00000311196.2 Q8IUM7-1
NPAS4ENST00000525148.1 linkn.533C>T non_coding_transcript_exon_variant Exon 4 of 7 1 ENSP00000433135.1 Q8IUM7-3
NPAS4ENST00000524617.1 linkn.-108C>T upstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
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
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.533C>T (p.P178L) alteration is located in exon 4 (coding exon 4) of the NPAS4 gene. This alteration results from a C to T substitution at nucleotide position 533, causing the proline (P) at amino acid position 178 to be replaced by a leucine (L). 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
0.11
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;T
Eigen
Benign
-0.064
Eigen_PC
Benign
0.087
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.43
N;N
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.3
.;N
REVEL
Benign
0.13
Sift
Uncertain
0.028
.;D
Sift4G
Uncertain
0.016
.;D
Polyphen
0.023
.;B
Vest4
0.39
MutPred
0.53
Loss of catalytic residue at P177 (P = 0.0138);Loss of catalytic residue at P177 (P = 0.0138);
MVP
0.58
MPC
0.45
ClinPred
0.85
D
GERP RS
4.8
Varity_R
0.11
gMVP
0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66190247; API