17-76468838-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001088.3(AANAT):c.92C>T(p.Thr31Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by PKA (size 0) in uniprot entity SNAT_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AANAT	NM_001088.3	c.92C>T	p.Thr31Ile	missense_variant	2/4	ENST00000392492.8
AANAT	NM_001166579.2	c.227C>T	p.Thr76Ile	missense_variant	5/7
AANAT	NR_110548.2	n.292C>T		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AANAT	ENST00000392492.8	c.92C>T	p.Thr31Ile	missense_variant	2/4	1	NM_001088.3	P1
AANAT	ENST00000250615.7	c.227C>T	p.Thr76Ile	missense_variant	5/7	1
AANAT	ENST00000585649.1	c.206C>T	p.Thr69Ile	missense_variant	1/3	1
AANAT	ENST00000587798.1	c.92C>T	p.Thr31Ile	missense_variant, NMD_transcript_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250176 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135452

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 210 AN: 1461256 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 726976

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000757

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.92C>T (p.T31I) alteration is located in exon 2 (coding exon 1) of the AANAT gene. This alteration results from a C to T substitution at nucleotide position 92, causing the threonine (T) at amino acid position 31 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Uncertain	-0.00010	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.84
MVP		0.83
MPC		0.38
ClinPred		0.36	T
GERP RS		4.3
Varity_R		0.48
gMVP		0.71

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: rs139765369; hg19: chr17-74464920;