chr17-76469729-G-A

Position:

chr17-76469729-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 15/21 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

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AANAT	NM_001088.3 linkuse as main transcript	c.383G>A	p.Arg128His	missense_variant	4/4	ENST00000392492.8
AANAT	NM_001166579.2 linkuse as main transcript	c.518G>A	p.Arg173His	missense_variant	7/7
AANAT	NR_110548.2 linkuse as main transcript	n.639G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8 linkuse as main transcript	c.383G>A	p.Arg128His	missense_variant	4/4	1	NM_001088.3	P1	Q16613-1
AANAT	ENST00000250615.7 linkuse as main transcript	c.518G>A	p.Arg173His	missense_variant	7/7	1			Q16613-2
AANAT	ENST00000587798.1 linkuse as main transcript	c.*160G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5
AANAT	ENST00000585649.1 linkuse as main transcript			downstream_gene_variant		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

GnomAD3 exomes

AF:

0.0000672

AC:

AN:

178606

Hom.:

AF XY:

0.0000513

AC XY:

AN XY:

97546

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 SAS exome

AF:

0.0000913

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

Gnomad4 AFR exome

AF:

0.000776

Gnomad4 AMR exome

AF:

0.0000791

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000511

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000740

Gnomad4 OTH exome

AF:

0.000173

GnomAD4 genome

AF:

0.000374

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000481

Hom.:

Bravo

AF:

0.000344

ESP6500AA

AF:

0.000690

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000670

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The c.383G>A (p.R128H) alteration is located in exon 4 (coding exon 3) of the AANAT gene. This alteration results from a G to A substitution at nucleotide position 383, causing the arginine (R) at amino acid position 128 to be replaced by a histidine (H). 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

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.17

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L

MutationTaster

Benign

0.95

D;D

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.70

N;N

REVEL

Benign

0.053

Sift

Benign

0.21

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0060

.;B

Vest4

0.14

MVP

0.18

MPC

0.068

ClinPred

0.023

GERP RS

-4.1

Varity_R

0.073

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over