17-76469814-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001088.3(AANAT):c.468C>T(p.Ala156=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,604,098 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: AANAT NM_001088.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.04

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-76469814-C-T is Benign according to our data. Variant chr17-76469814-C-T is described in ClinVar as [Benign]. Clinvar id is 714416.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00181 (2632/1451750) while in subpopulation EAS AF= 0.0305 (1198/39244). AF 95% confidence interval is 0.0291. There are 38 homozygotes in gnomad4_exome. There are 1299 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.468C>T	p.Ala156=	synonymous_variant	4/4	ENST00000392492.8
AANAT	NM_001166579.2	c.603C>T	p.Ala201=	synonymous_variant	7/7
AANAT	NR_110548.2	n.724C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.468C>T	p.Ala156=	synonymous_variant	4/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.603C>T	p.Ala201=	synonymous_variant	7/7	1
AANAT	ENST00000587798.1	c.*245C>T		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00326 AC: 748 AN: 229192 Hom.: 14 AF XY: 0.00305 AC XY: 383 AN XY: 125410

Gnomad AFR exome AF: 0.0000720

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.000420

Gnomad EAS exome AF: 0.0165

Gnomad SAS exome AF: 0.000486

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.00372

GnomAD4 exome AF: 0.00181 AC: 2632 AN: 1451750 Hom.: 38 Cov.: 31 AF XY: 0.00180 AC XY: 1299 AN XY: 721430

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.000387

Gnomad4 EAS exome AF: 0.0305

Gnomad4 SAS exome AF: 0.000791

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74500

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000778

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.34
Dann	Benign	0.91

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: rs2071031; hg19: chr17-74465896;