rs141006262

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001088.3(AANAT):​c.86G>A​(p.Arg29His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,450 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

AANAT
NM_001088.3 missense

Scores

4
8
7

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 9.31

Publications

3 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011256874).
BP6
Variant 17-76468832-G-A is Benign according to our data. Variant chr17-76468832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 777222.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AANATNM_001088.3 linkc.86G>A p.Arg29His missense_variant Exon 2 of 4 ENST00000392492.8 NP_001079.1 Q16613-1F1T0I5
AANATNM_001166579.2 linkc.221G>A p.Arg74His missense_variant Exon 5 of 7 NP_001160051.1 Q16613-2
AANATNR_110548.2 linkn.286G>A non_coding_transcript_exon_variant Exon 2 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AANATENST00000392492.8 linkc.86G>A p.Arg29His missense_variant Exon 2 of 4 1 NM_001088.3 ENSP00000376282.2 Q16613-1
AANATENST00000250615.7 linkc.221G>A p.Arg74His missense_variant Exon 5 of 7 1 ENSP00000250615.2 Q16613-2
AANATENST00000585649.1 linkc.200G>A p.Arg67His missense_variant Exon 1 of 3 1 ENSP00000468717.1 K7ESH7
AANATENST00000587798.1 linkn.86G>A non_coding_transcript_exon_variant Exon 2 of 4 5 ENSP00000468239.1 K7ERF6

Frequencies

GnomAD3 genomes
AF:
0.00124
AC:
189
AN:
152124
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00444
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000316
AC:
79
AN:
249984
AF XY:
0.000266
show subpopulations
Gnomad AFR exome
AF:
0.00464
Gnomad AMR exome
AF:
0.000116
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:
0.000120
AC:
175
AN:
1461208
Hom.:
0
Cov.:
31
AF XY:
0.000109
AC XY:
79
AN XY:
726938
show subpopulations
African (AFR)
AF:
0.00448
AC:
150
AN:
33480
American (AMR)
AF:
0.000179
AC:
8
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52798
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111984
Other (OTH)
AF:
0.000215
AC:
13
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.467
Heterozygous variant carriers
0
11
23
34
46
57
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00126
AC:
192
AN:
152242
Hom.:
2
Cov.:
32
AF XY:
0.00130
AC XY:
97
AN XY:
74462
show subpopulations
African (AFR)
AF:
0.00450
AC:
187
AN:
41534
American (AMR)
AF:
0.000327
AC:
5
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68002
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
8
17
25
34
42
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.000360
Hom.:
0
Bravo
AF:
0.00141
ESP6500AA
AF:
0.00318
AC:
14
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000420
AC:
51

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Apr 24, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
.;T;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.011
T;T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.9
.;M;.
PhyloP100
9.3
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.5
N;N;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.0010
D;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.81
MVP
0.83
MPC
0.40
ClinPred
0.14
T
GERP RS
4.3
PromoterAI
0.0046
Neutral
Varity_R
0.33
gMVP
0.66
Mutation Taster
=63/37
polymorphism

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

Other links and lift over

dbSNP: rs141006262; hg19: chr17-74464914; API