17-76469889-C-A

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.543C>A(p.Ile181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,579,736 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: AANAT NM_001088.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.44

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=-0.71).
• BP6: Variant 17-76469889-C-A is Benign according to our data. Variant chr17-76469889-C-A is described in ClinVar as [Benign]. Clinvar id is 788909.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1722/152354) while in subpopulation AFR AF= 0.0387 (1608/41576). AF 95% confidence interval is 0.0371. There are 34 homozygotes in gnomad4. There are 804 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.543C>A	p.Ile181=	synonymous_variant	4/4	ENST00000392492.8
AANAT	NM_001166579.2	c.678C>A	p.Ile226=	synonymous_variant	7/7
AANAT	NR_110548.2	n.799C>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.543C>A	p.Ile181=	synonymous_variant	4/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.678C>A	p.Ile226=	synonymous_variant	7/7	1
AANAT	ENST00000587798.1	c.*320C>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1722 AN: 152236 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

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: 0.000147

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00292 AC: 563 AN: 192970 Hom.: 13 AF XY: 0.00214 AC XY: 223 AN XY: 104294

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000791

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.00118 AC: 1689 AN: 1427382 Hom.: 38 Cov.: 31 AF XY: 0.00106 AC XY: 749 AN XY: 707220

Gnomad4 AFR exome AF: 0.0417

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000734

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000411

Gnomad4 OTH exome AF: 0.00271

GnomAD4 genome AF: 0.0113 AC: 1722 AN: 152354 Hom.: 34 Cov.: 32 AF XY: 0.0108 AC XY: 804 AN XY: 74504

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.0134

Asia WGS AF: 0.00115 AC: 4 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

Jul 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.0
Dann	Benign	0.65

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: rs58504104; hg19: chr17-74465971;