Genetic Variant NPAS3:p.Thr736Thr (chr14-33800515-C-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_001164749.2(NPAS3):c.2208C>G(p.Thr736Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,413,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

NPAS3
NM_001164749.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.186

Publications

9 publications found

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]

NPAS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=0.186 with no splicing effect.

BS2

High AC in GnomAd4 at 22 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164749.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPAS3	NM_001164749.2	MANE Select	c.2208C>G	p.Thr736Thr	synonymous	Exon 12 of 12	NP_001158221.1
NPAS3	NM_173159.3		c.2169C>G	p.Thr723Thr	synonymous	Exon 12 of 12	NP_775182.1
NPAS3	NM_001394988.1		c.2163C>G	p.Thr721Thr	synonymous	Exon 12 of 12	NP_001381917.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPAS3	ENST00000356141.9	TSL:1 MANE Select	c.2208C>G	p.Thr736Thr	synonymous	Exon 12 of 12	ENSP00000348460.4
NPAS3	ENST00000357798.9	TSL:1	c.2169C>G	p.Thr723Thr	synonymous	Exon 12 of 12	ENSP00000350446.5
NPAS3	ENST00000548645.5	TSL:1	c.2118C>G	p.Thr706Thr	synonymous	Exon 11 of 11	ENSP00000448916.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00145

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000317

AC:

AN:

1261778

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

620222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24066

American (AMR)

AF:

0.00

AC:

AN:

12418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19928

East Asian (EAS)

AF:

0.00

AC:

AN:

27210

South Asian (SAS)

AF:

0.00

AC:

AN:

60246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3606

European-Non Finnish (NFE)

AF:

0.00000391

AC:

AN:

1023358

Other (OTH)

AF:

0.00

AC:

AN:

51684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000145

AC:

AN:

151226

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73860

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41306

American (AMR)

AF:

0.00145

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67714

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

2290

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.5

(source)

DANN

Benign

0.46

PhyloP100

0.19

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over