chr11-66422745-C-T

Variant summary

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

The NM_178864.4(NPAS4):​c.502C>T​(p.Leu168Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,846 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NPAS4
NM_178864.4 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83
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=0.41952544).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPAS4NM_178864.4 linkc.502C>T p.Leu168Phe 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.502C>T p.Leu168Phe missense_variant Exon 4 of 8 1 NM_178864.4 ENSP00000311196.2 Q8IUM7-1
NPAS4ENST00000525148.1 linkn.502C>T non_coding_transcript_exon_variant Exon 4 of 7 1 ENSP00000433135.1 Q8IUM7-3
NPAS4ENST00000524617.1 linkn.-139C>T upstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251442
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727224
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
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
Apr 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.502C>T (p.L168F) 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 502, causing the leucine (L) at amino acid position 168 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
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
.;D
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Benign
0.57
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.42
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.1
.;D
REVEL
Benign
0.23
Sift
Benign
0.11
.;T
Sift4G
Uncertain
0.020
.;D
Polyphen
1.0
.;D
Vest4
0.36
MutPred
0.35
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.55
MPC
0.95
ClinPred
0.98
D
GERP RS
5.7
Varity_R
0.32
gMVP
0.63

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

LitVar

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

Other links and lift over

dbSNP: rs1480238880; hg19: chr11-66190216; API