chr17-76469833-G-C

Variant summary

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

The NM_001088.3(AANAT):ā€‹c.487G>Cā€‹(p.Ala163Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,604,934 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 32)
Exomes š‘“: 0.00015 ( 0 hom. )

Consequence

AANAT
NM_001088.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0360
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 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=0.08651492).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AANATNM_001088.3 linkc.487G>C p.Ala163Pro missense_variant Exon 4 of 4 ENST00000392492.8 NP_001079.1 Q16613-1F1T0I5
AANATNM_001166579.2 linkc.622G>C p.Ala208Pro missense_variant Exon 7 of 7 NP_001160051.1 Q16613-2
AANATNR_110548.2 linkn.743G>C non_coding_transcript_exon_variant Exon 4 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AANATENST00000392492.8 linkc.487G>C p.Ala163Pro missense_variant Exon 4 of 4 1 NM_001088.3 ENSP00000376282.2 Q16613-1
AANATENST00000250615.7 linkc.622G>C p.Ala208Pro missense_variant Exon 7 of 7 1 ENSP00000250615.2 Q16613-2
AANATENST00000587798.1 linkn.*264G>C non_coding_transcript_exon_variant Exon 4 of 4 5 ENSP00000468239.1 K7ERF6
AANATENST00000587798.1 linkn.*264G>C 3_prime_UTR_variant Exon 4 of 4 5 ENSP00000468239.1 K7ERF6

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152244
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000563
AC:
13
AN:
230802
Hom.:
0
AF XY:
0.0000635
AC XY:
8
AN XY:
125934
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000126
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000154
AC:
224
AN:
1452690
Hom.:
0
Cov.:
31
AF XY:
0.000152
AC XY:
110
AN XY:
722042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.000200
Gnomad4 OTH exome
AF:
0.0000334
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000662
AC:
8

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.487G>C (p.A163P) alteration is located in exon 4 (coding exon 3) of the AANAT gene. This alteration results from a G to C substitution at nucleotide position 487, causing the alanine (A) at amino acid position 163 to be replaced by a proline (P). 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
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
0.018
DANN
Benign
0.92
DEOGEN2
Benign
0.11
.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.096
N
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.0084
T
MetaRNN
Benign
0.087
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
.;L
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.030
N;N
REVEL
Benign
0.032
Sift
Benign
0.22
T;T
Sift4G
Benign
0.20
T;T
Polyphen
0.0010
.;B
Vest4
0.093
MutPred
0.52
.;Loss of stability (P = 0.1252);
MVP
0.061
MPC
0.071
ClinPred
0.036
T
GERP RS
-5.7
Varity_R
0.10
gMVP
0.78

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: rs371445287; hg19: chr17-74465915; API