17-76459497-T-C

Variant names:

• chr17-76459497-T-C
• rs11077821
• ENST00000250615.7:c.-456+131T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000250615.7(AANAT):​c.-456+131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 152,244 control chromosomes in the GnomAD database, including 51,359 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (51343 hom., cov: 33)
  • Exomes 𝑓: 0.86 (16 hom.)
• Consequence: AANAT ENST00000250615.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AANAT	NM_001166579.2	c.-456+131T>C		intron_variant	Intron 2 of 6		NP_001160051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AANAT	ENST00000250615.7	c.-456+131T>C		intron_variant	Intron 2 of 6	1		ENSP00000250615.2

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123765 AN: 152082 Hom.: 51314 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.778

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.923

Gnomad FIN AF: 0.900

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.822

GnomAD4 exome AF: 0.864 AC: 38 AN: 44 Hom.: 16 AF XY: 0.875 AC XY: 28 AN XY: 32

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.906 AC: 29 AN: 32

Other (OTH) AF: 1.00 AC: 2 AN: 2

GnomAD4 genome AF: 0.814 AC: 123837 AN: 152200 Hom.: 51343 Cov.: 33 AF XY: 0.819 AC XY: 60978 AN XY: 74432

African (AFR) AF: 0.648 AC: 26892 AN: 41488

American (AMR) AF: 0.870 AC: 13314 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2991 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5172 AN: 5176

South Asian (SAS) AF: 0.923 AC: 4458 AN: 4832

European-Finnish (FIN) AF: 0.900 AC: 9541 AN: 10602

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58769 AN: 68014

Other (OTH) AF: 0.824 AC: 1740 AN: 2112

Alfa AF: 0.845 Hom.: 26140

Bravo AF: 0.802

Asia WGS AF: 0.945 AC: 3284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.8
DANN	Benign	0.77
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11077821; hg19: chr17-74455579;