chr17-76468754-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.47

Publications

6 publications found

Variant links:

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]

AANAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
AANAT	NM_001088.3 link	c.8C>T	p.Thr3Met	missense_variant	Exon 2 of 4	ENST00000392492.8	NP_001079.1	Q16613-1F1T0I5
AANAT	NM_001166579.2 link	c.143C>T	p.Thr48Met	missense_variant	Exon 5 of 7		NP_001160051.1	Q16613-2
AANAT	NR_110548.2 link	n.208C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AANAT	ENST00000392492.8 link	c.8C>T	p.Thr3Met	missense_variant	Exon 2 of 4	1	NM_001088.3	ENSP00000376282.2	Q16613-1
AANAT	ENST00000250615.7 link	c.143C>T	p.Thr48Met	missense_variant	Exon 5 of 7	1		ENSP00000250615.2	Q16613-2
AANAT	ENST00000585649.1 link	c.122C>T	p.Thr41Met	missense_variant	Exon 1 of 3	1		ENSP00000468717.1	K7ESH7
AANAT	ENST00000587798.1 link	n.8C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000468239.1	K7ERF6

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2424

AN:

152120

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00499

AC:

1222

AN:

244984

AF XY:

0.00392

show subpopulations

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 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.:

Cov.:

AF XY:

0.00224

AC XY:

1626

AN XY:

726026

show subpopulations

African (AFR)

AF:

0.0543

AC:

1815

AN:

33436

American (AMR)

AF:

0.00492

AC:

219

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00441

AC:

115

AN:

26066

East Asian (EAS)

AF:

0.000202

AC:

AN:

39636

South Asian (SAS)

AF:

0.00320

AC:

275

AN:

85970

European-Finnish (FIN)

AF:

0.0000381

AC:

AN:

52428

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000532

AC:

591

AN:

1111382

Other (OTH)

AF:

0.00523

AC:

315

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

206

412

618

824

1030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0160

AC:

2436

AN:

152238

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1147

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0522

AC:

2166

AN:

41514

American (AMR)

AF:

0.00869

AC:

133

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000971

AC:

AN:

67998

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.0184

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0532

AC:

234

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00543

AC:

659

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.046

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.066

.;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.42

.;N;.

PhyloP100

-1.5

PrimateAI

Benign

0.21

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

GERP RS

-4.9

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.016

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(source)

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

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chr17-76468754-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over