17-76469737-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3
The NM_001088.3(AANAT):c.391C>T(p.Arg131Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000519 in 1,559,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131Q) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
AANAT
NM_001088.3 missense
NM_001088.3 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 5.54
Publications
0 publications found
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]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.79
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AANAT | NM_001088.3 | c.391C>T | p.Arg131Trp | missense_variant | Exon 4 of 4 | ENST00000392492.8 | NP_001079.1 | |
| AANAT | NM_001166579.2 | c.526C>T | p.Arg176Trp | missense_variant | Exon 7 of 7 | NP_001160051.1 | ||
| AANAT | NR_110548.2 | n.647C>T | non_coding_transcript_exon_variant | Exon 4 of 4 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
4
AN:
152236
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000220 AC: 4AN: 181882 AF XY: 0.0000100 show subpopulations
GnomAD2 exomes
AF:
AC:
4
AN:
181882
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000547 AC: 77AN: 1407030Hom.: 0 Cov.: 31 AF XY: 0.0000533 AC XY: 37AN XY: 694040 show subpopulations
GnomAD4 exome
AF:
AC:
77
AN:
1407030
Hom.:
Cov.:
31
AF XY:
AC XY:
37
AN XY:
694040
show subpopulations
African (AFR)
AF:
AC:
1
AN:
32332
American (AMR)
AF:
AC:
0
AN:
38196
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23962
East Asian (EAS)
AF:
AC:
0
AN:
37930
South Asian (SAS)
AF:
AC:
0
AN:
79500
European-Finnish (FIN)
AF:
AC:
0
AN:
48352
Middle Eastern (MID)
AF:
AC:
0
AN:
5158
European-Non Finnish (NFE)
AF:
AC:
75
AN:
1083720
Other (OTH)
AF:
AC:
1
AN:
57880
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366 show subpopulations
GnomAD4 genome
AF:
AC:
4
AN:
152236
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74366
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41468
American (AMR)
AF:
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
1
AN:
5194
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
2
AN:
68036
Other (OTH)
AF:
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.600
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Apr 09, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.391C>T (p.R131W) alteration is located in exon 4 (coding exon 3) of the AANAT gene. This alteration results from a C to T substitution at nucleotide position 391, causing the arginine (R) at amino acid position 131 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
.;M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Benign
D;T
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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