17-76468754-C-T

Position:

• chr17-76468754-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001088.3(AANAT):​c.8C>T​(p.Thr3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,611,714 control chromosomes in the GnomAD database, including 131 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (66 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019198656).
• BP6: Variant 17-76468754-C-T is Benign according to our data. Variant chr17-76468754-C-T is described in ClinVar as [Benign]. Clinvar id is 788908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.8C>T	p.Thr3Met	missense_variant	2/4	ENST00000392492.8
AANAT	NM_001166579.2	c.143C>T	p.Thr48Met	missense_variant	5/7
AANAT	NR_110548.2	n.208C>T		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.8C>T	p.Thr3Met	missense_variant	2/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.143C>T	p.Thr48Met	missense_variant	5/7	1
AANAT	ENST00000585649.1	c.122C>T	p.Thr41Met	missense_variant	1/3	1
AANAT	ENST00000587798.1	c.8C>T	p.Thr3Met	missense_variant, NMD_transcript_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2424 AN: 152120 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00499 AC: 1222 AN: 244984 Hom.: 28 AF XY: 0.00392 AC XY: 522 AN XY: 133138

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00464

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.0000488

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00235 AC: 3432 AN: 1459476 Hom.: 66 Cov.: 31 AF XY: 0.00224 AC XY: 1626 AN XY: 726026

Gnomad4 AFR exome AF: 0.0543

Gnomad4 AMR exome AF: 0.00492

Gnomad4 ASJ exome AF: 0.00441

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000532

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0160 AC: 2436 AN: 152238 Hom.: 65 Cov.: 32 AF XY: 0.0154 AC XY: 1147 AN XY: 74450

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00435 Hom.: 4

Bravo AF: 0.0184

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0532 AC: 234

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00543 AC: 659

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.046
DANN	Benign	0.73
DEOGEN2	Benign	0.066	.;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.050	N;N;.
REVEL	Benign	0.061
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0070	.;B;.
Vest4		0.13
MVP		0.16
MPC		0.073
ClinPred		0.0058	T
GERP RS		-4.9
Varity_R		0.016
gMVP		0.19

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: rs61739395; hg19: chr17-74464836; COSMIC: COSV51684699; COSMIC: COSV51684699;