Genetic Variant NPAS3:p.Thr736Thr (chr14-33800515-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001164749.2(NPAS3):c.2208C>T(p.Thr736Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,412,672 control chromosomes in the GnomAD database, including 17,229 homozygotes. 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 0.12 ( 1332 hom., cov: 32)

Exomes 𝑓: 0.15 ( 15897 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 -13 ACMG points.

BP4

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

BP7

Synonymous conserved (PhyloP=0.186 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS3	NM_001164749.2 link	c.2208C>T	p.Thr736Thr	synonymous_variant	Exon 12 of 12	ENST00000356141.9	NP_001158221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS3	ENST00000356141.9 link	c.2208C>T	p.Thr736Thr	synonymous_variant	Exon 12 of 12	1	NM_001164749.2	ENSP00000348460.4

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18423

AN:

151178

Hom.:

1332

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0695

Gnomad AMI

AF:

0.234

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.0974

Gnomad EAS

AF:

0.0113

Gnomad SAS

AF:

0.0793

Gnomad FIN

AF:

0.0634

Gnomad MID

AF:

0.0962

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.127

AC:

5055

AN:

39738

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.0552

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.0181

Gnomad FIN exome

AF:

0.0738

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.153

AC:

193390

AN:

1261388

Hom.:

15897

Cov.:

AF XY:

0.152

AC XY:

94142

AN XY:

620000

show subpopulations

African (AFR)

AF:

0.0628

AC:

1512

AN:

24060

American (AMR)

AF:

0.169

AC:

2092

AN:

12388

Ashkenazi Jewish (ASJ)

AF:

0.0942

AC:

1875

AN:

19908

East Asian (EAS)

AF:

0.0221

AC:

602

AN:

27208

South Asian (SAS)

AF:

0.0860

AC:

5181

AN:

60228

European-Finnish (FIN)

AF:

0.0762

AC:

2989

AN:

39248

Middle Eastern (MID)

AF:

0.107

AC:

387

AN:

3606

European-Non Finnish (NFE)

AF:

0.168

AC:

171649

AN:

1023086

Other (OTH)

AF:

0.138

AC:

7103

AN:

51656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

8233

16466

24699

32932

41165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6246

12492

18738

24984

31230

<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:

0.122

AC:

18432

AN:

151284

Hom.:

1332

Cov.:

AF XY:

0.117

AC XY:

8638

AN XY:

73944

show subpopulations

African (AFR)

AF:

0.0695

AC:

2878

AN:

41414

American (AMR)

AF:

0.162

AC:

2465

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.0974

AC:

337

AN:

3460

East Asian (EAS)

AF:

0.0111

AC:

AN:

5114

South Asian (SAS)

AF:

0.0786

AC:

379

AN:

4824

European-Finnish (FIN)

AF:

0.0634

AC:

652

AN:

10292

Middle Eastern (MID)

AF:

0.100

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.164

AC:

11134

AN:

67686

Other (OTH)

AF:

0.138

AC:

288

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

786

1572

2358

3144

3930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.147

Hom.:

2290

Bravo

AF:

0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.4

(source)

DANN

Benign

0.86

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over