17-76469830-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001088.3(AANAT):​c.484G>A​(p.Asp162Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AANAT
NM_001088.3 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09
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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19458088).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AANATNM_001088.3 linkuse as main transcriptc.484G>A p.Asp162Asn missense_variant 4/4 ENST00000392492.8
AANATNM_001166579.2 linkuse as main transcriptc.619G>A p.Asp207Asn missense_variant 7/7
AANATNR_110548.2 linkuse as main transcriptn.740G>A non_coding_transcript_exon_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AANATENST00000392492.8 linkuse as main transcriptc.484G>A p.Asp162Asn missense_variant 4/41 NM_001088.3 P1Q16613-1
AANATENST00000250615.7 linkuse as main transcriptc.619G>A p.Asp207Asn missense_variant 7/71 Q16613-2
AANATENST00000587798.1 linkuse as main transcriptc.*261G>A 3_prime_UTR_variant, NMD_transcript_variant 4/45

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000130
AC:
3
AN:
231258
Hom.:
0
AF XY:
0.00000792
AC XY:
1
AN XY:
126258
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000303
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000194
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1452832
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000229
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000828
AC:
1

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 submitterclinical testingAmbry GeneticsJun 14, 2022The c.484G>A (p.D162N) 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 484, causing the aspartic acid (D) at amino acid position 162 to be replaced by an asparagine (N). 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
0.093
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
.;T
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.28
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.19
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.9
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.33
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Benign
0.20
Sift
Uncertain
0.021
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
0.011
.;B
Vest4
0.13
MutPred
0.56
.;Loss of helix (P = 0.2022);
MVP
0.38
MPC
0.056
ClinPred
0.82
D
GERP RS
3.0
Varity_R
0.39
gMVP
0.54

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.

Other links and lift over

dbSNP: rs773528016; hg19: chr17-74465912; API