14-33774465-A-T

Variant names:

• chr14-33774465-A-T
• NM_001164749.2:c.981A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164749.2(NPAS3):​c.981A>T​(p.Arg327Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS3 NM_001164749.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS3	NM_001164749.2	c.981A>T	p.Arg327Ser	missense_variant	Exon 8 of 12	ENST00000356141.9	NP_001158221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS3	ENST00000356141.9	c.981A>T	p.Arg327Ser	missense_variant	Exon 8 of 12	1	NM_001164749.2	ENSP00000348460.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.981A>T (p.R327S) alteration is located in exon 8 (coding exon 8) of the NPAS3 gene. This alteration results from a A to T substitution at nucleotide position 981, causing the arginine (R) at amino acid position 327 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.99, 0.99	.;.;D;D;D;D
Vest4		0.91, 0.90, 0.84, 0.91
MutPred		0.47		.;.;.;.;Loss of catalytic residue at M332 (P = 0.0936);.;
MVP		0.57
MPC		1.7
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.69
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -6

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: chr14-34243671;