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GeneBe

14-33215335-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001164749.2(NPAS3):c.294T>C(p.Ile98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,590,724 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 9 hom., cov: 33)
Exomes 𝑓: 0.00069 ( 6 hom. )

Consequence

NPAS3
NM_001164749.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.89
Variant links:
Genes affected
NPAS3 (HGNC:19311): (neuronal PAS domain protein 3) This gene encodes a member of the basic helix-loop-helix and PAS domain-containing family of transcription factors. The encoded protein is localized to the nucleus and may regulate genes involved in neurogenesis. Chromosomal abnormalities that affect the coding potential of this gene are associated with schizophrenia and cognitive disability. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-33215335-T-C is Benign according to our data. Variant chr14-33215335-T-C is described in ClinVar as [Benign]. Clinvar id is 786617.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.89 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00518 (788/152256) while in subpopulation AFR AF= 0.0163 (678/41548). AF 95% confidence interval is 0.0153. There are 9 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 776 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPAS3NM_001164749.2 linkuse as main transcriptc.294T>C p.Ile98= synonymous_variant 3/12 ENST00000356141.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPAS3ENST00000356141.9 linkuse as main transcriptc.294T>C p.Ile98= synonymous_variant 3/121 NM_001164749.2 A2Q8IXF0-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00510
AC:
776
AN:
152138
Hom.:
8
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0161
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00491
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00166
AC:
418
AN:
251220
Hom.:
5
AF XY:
0.00138
AC XY:
188
AN XY:
135764
show subpopulations
Gnomad AFR exome
AF:
0.0165
Gnomad AMR exome
AF:
0.00182
Gnomad ASJ exome
AF:
0.00268
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00124
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.000689
AC:
991
AN:
1438468
Hom.:
6
Cov.:
26
AF XY:
0.000673
AC XY:
483
AN XY:
717276
show subpopulations
Gnomad4 AFR exome
AF:
0.0158
Gnomad4 AMR exome
AF:
0.00208
Gnomad4 ASJ exome
AF:
0.00285
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00104
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000807
Gnomad4 OTH exome
AF:
0.00203
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00518
AC:
788
AN:
152256
Hom.:
9
Cov.:
33
AF XY:
0.00508
AC XY:
378
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0163
Gnomad4 AMR
AF:
0.00491
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00324
Hom.:
1
Bravo
AF:
0.00577
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000296

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeNov 16, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
Cadd
Benign
8.6
Dann
Benign
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs139734921; hg19: chr14-33684541; API