14-33676349-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001164749.2(NPAS3):c.697G>A(p.Ala233Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,444,056 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: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: NPAS3 NM_001164749.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3590123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPAS3	NM_001164749.2	c.697G>A	p.Ala233Thr	missense_variant	6/12	ENST00000356141.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPAS3	ENST00000356141.9	c.697G>A	p.Ala233Thr	missense_variant	6/12	1	NM_001164749.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1444056 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000752

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.697G>A (p.A233T) alteration is located in exon 6 (coding exon 6) of the NPAS3 gene. This alteration results from a G to A substitution at nucleotide position 697, causing the alanine (A) at amino acid position 233 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;.;.;T;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.043	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.043	D;D;T;T;T;T;T;T
Polyphen		0.27, 0.86, 0.86, 0.98, 1.0	.;.;B;P;P;D;.;D
Vest4		0.78, 0.78, 0.77, 0.79, 0.78, 0.77, 0.79
MutPred		0.31		.;.;.;.;Gain of glycosylation at A233 (P = 0.0067);.;.;.;
MVP		0.25
MPC		1.2
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.17
gMVP		0.36

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

Other links and lift over

dbSNP: rs1257236436; hg19: chr14-34145555;