17-76469812-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001088.3(AANAT):ā€‹c.466G>Cā€‹(p.Ala156Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,451,584 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

AANAT
NM_001088.3 missense

Scores

3
14
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AANATNM_001088.3 linkc.466G>C p.Ala156Pro missense_variant Exon 4 of 4 ENST00000392492.8 NP_001079.1 Q16613-1F1T0I5
AANATNM_001166579.2 linkc.601G>C p.Ala201Pro missense_variant Exon 7 of 7 NP_001160051.1 Q16613-2
AANATNR_110548.2 linkn.722G>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.466G>C p.Ala156Pro missense_variant Exon 4 of 4 1 NM_001088.3 ENSP00000376282.2 Q16613-1
AANATENST00000250615.7 linkc.601G>C p.Ala201Pro missense_variant Exon 7 of 7 1 ENSP00000250615.2 Q16613-2
AANATENST00000587798.1 linkn.*243G>C non_coding_transcript_exon_variant Exon 4 of 4 5 ENSP00000468239.1 K7ERF6
AANATENST00000587798.1 linkn.*243G>C 3_prime_UTR_variant Exon 4 of 4 5 ENSP00000468239.1 K7ERF6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000875
AC:
2
AN:
228618
Hom.:
0
AF XY:
0.0000160
AC XY:
2
AN XY:
125110
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:
0.0000348
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000984
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1451584
Hom.:
0
Cov.:
31
AF XY:
0.0000180
AC XY:
13
AN XY:
721352
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:
0.0000354
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 26, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.466G>C (p.A156P) 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 466, causing the alanine (A) at amino acid position 156 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
Uncertain
0.53
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.060
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
.;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Pathogenic
3.2
.;M
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.022
D;D
Sift4G
Uncertain
0.016
D;D
Polyphen
1.0
.;D
Vest4
0.80
MutPred
0.78
.;Gain of sheet (P = 0.1208);
MVP
0.40
MPC
0.40
ClinPred
0.95
D
GERP RS
5.1
Varity_R
0.96
gMVP
0.95

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: rs1286672780; hg19: chr17-74465894; API