chr17-76469289-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001088.3(AANAT):​c.280A>G​(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AANAT
NM_001088.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

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]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21777764).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AANATNM_001088.3 linkc.280A>G p.Ile94Val missense_variant Exon 3 of 4 ENST00000392492.8 NP_001079.1 Q16613-1F1T0I5
AANATNM_001166579.2 linkc.415A>G p.Ile139Val missense_variant Exon 6 of 7 NP_001160051.1 Q16613-2
AANATNR_110548.2 linkn.536A>G non_coding_transcript_exon_variant Exon 3 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AANATENST00000392492.8 linkc.280A>G p.Ile94Val missense_variant Exon 3 of 4 1 NM_001088.3 ENSP00000376282.2 Q16613-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 16, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.280A>G (p.I94V) alteration is located in exon 3 (coding exon 2) of the AANAT gene. This alteration results from a A to G substitution at nucleotide position 280, causing the isoleucine (I) at amino acid position 94 to be replaced by a valine (V). 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
0.12
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
.;T;.
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.039
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
.;L;.
PhyloP100
3.4
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.44
N;N;.
REVEL
Benign
0.059
Sift
Benign
0.28
T;T;.
Sift4G
Benign
0.091
T;T;T
Polyphen
0.0050
.;B;.
Vest4
0.34
MutPred
0.53
.;Loss of sheet (P = 0.0315);.;
MVP
0.38
MPC
0.054
ClinPred
0.79
D
GERP RS
3.9
Varity_R
0.15
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs554635215; hg19: chr17-74465371; API