17-76469731-G-A

Position:

• chr17-76469731-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001088.3(AANAT):​c.385G>A​(p.Ala129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,556,692 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (18 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.654

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031598508).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000939 (143/152328) while in subpopulation EAS AF= 0.0224 (116/5174). AF 95% confidence interval is 0.0191. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.385G>A	p.Ala129Thr	missense_variant	4/4	ENST00000392492.8
AANAT	NM_001166579.2	c.520G>A	p.Ala174Thr	missense_variant	7/7
AANAT	NR_110548.2	n.641G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.385G>A	p.Ala129Thr	missense_variant	4/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.520G>A	p.Ala174Thr	missense_variant	7/7	1
AANAT	ENST00000587798.1	c.*162G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5
AANAT	ENST00000585649.1			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 141 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00225 AC: 409 AN: 181648 Hom.: 7 AF XY: 0.00208 AC XY: 207 AN XY: 99314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0258

Gnomad SAS exome AF: 0.000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000762

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.000763 AC: 1072 AN: 1404364 Hom.: 18 Cov.: 31 AF XY: 0.000732 AC XY: 507 AN XY: 692244

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.000105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0226

Gnomad4 SAS exome AF: 0.000571

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000637

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000580 Hom.: 1

Bravo AF: 0.00116

ExAC AF: 0.00171 AC: 205

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Delayed sleep phase syndrome, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.5
DANN	Benign	0.84
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.015	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.0070
Sift	Benign	0.81	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	.;B
Vest4		0.045
MVP		0.067
MPC		0.056
ClinPred		0.0035	T
GERP RS		-1.2
Varity_R		0.041
gMVP		0.33

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

Other links and lift over

dbSNP: rs28936679; hg19: chr17-74465813; COSMIC: COSV99166180; COSMIC: COSV99166180;