Genetic Variant NM_001088.3:c.383G>A (chr17-76469729-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001088.3(AANAT):c.383G>A(p.Arg128His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000689 in 1,553,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R128R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

AANAT
NM_001088.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Publications

0 publications found

Variant links:

Genes affected

AANAT (HGNC:19): (aralkylamine N-acetyltransferase) The protein encoded by this gene belongs to the acetyltransferase superfamily. It is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. Melatonin is essential for the function of the circadian clock that influences activity and sleep. This enzyme is regulated by cAMP-dependent phosphorylation that promotes its interaction with 14-3-3 proteins and thus protects the enzyme against proteasomal degradation. This gene may contribute to numerous genetic diseases such as delayed sleep phase syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

AANAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023429155).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001088.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AANAT	NM_001088.3	MANE Select	c.383G>A	p.Arg128His	missense	Exon 4 of 4	NP_001079.1	F1T0I5
AANAT	NM_001166579.2		c.518G>A	p.Arg173His	missense	Exon 7 of 7	NP_001160051.1	Q16613-2
AANAT	NR_110548.2		n.639G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AANAT	ENST00000392492.8	TSL:1 MANE Select	c.383G>A	p.Arg128His	missense	Exon 4 of 4	ENSP00000376282.2	Q16613-1
AANAT	ENST00000250615.7	TSL:1	c.518G>A	p.Arg173His	missense	Exon 7 of 7	ENSP00000250615.2	Q16613-2
AANAT	ENST00000878873.1		c.383G>A	p.Arg128His	missense	Exon 4 of 4	ENSP00000548932.1

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000672

AC:

AN:

178606

AF XY:

0.0000513

show subpopulations

Gnomad AFR exome

AF:

0.000798

Gnomad AMR exome

AF:

0.0000370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1401200

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

690360

show subpopulations

African (AFR)

AF:

0.000776

AC:

AN:

32234

American (AMR)

AF:

0.0000791

AC:

AN:

37944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23478

East Asian (EAS)

AF:

0.00

AC:

AN:

37924

South Asian (SAS)

AF:

0.0000511

AC:

AN:

78224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5140

European-Non Finnish (NFE)

AF:

0.00000740

AC:

AN:

1080786

Other (OTH)

AF:

0.000173

AC:

AN:

57722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000374

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41460

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Age Distribution

Genome 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

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000344

ESP6500AA

AF:

0.000690

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000670

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.023

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

1.7

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.70

REVEL

Benign

0.053

Sift

Benign

0.21

Sift4G

Benign

0.31

Polyphen

0.0060

Vest4

0.14

MVP

0.18

MPC

0.068

ClinPred

0.023

GERP RS

-4.1

Varity_R

0.073

gMVP

0.45

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over