Genetic Variant NPAS3:p.Thr736Thr (chr14-33800515-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001164749.2(NPAS3):c.2208C>A(p.Thr736Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,261,776 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: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP7

Synonymous conserved (PhyloP=0.186 with no splicing effect.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000159

AC:

AN:

1261776

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

620220

show subpopulations

African (AFR)

AF:

0.0000416

AC:

AN:

24066

American (AMR)

AF:

0.00

AC:

AN:

12418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19928

East Asian (EAS)

AF:

0.0000368

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:

0.00

AC:

AN:

1023356

Other (OTH)

AF:

0.00

AC:

AN:

51684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

Alfa

AF:

0.00

Hom.:

2290

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

1.4

(source)

DANN

Benign

0.72

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over