chr17-76468828-C-T

Variant names:

• chr17-76468828-C-T
• rs373005685
• NM_001088.3:c.82C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001088.3(AANAT):​c.82C>T​(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AANAT	NM_001088.3	c.82C>T	p.Arg28Trp	missense_variant	Exon 2 of 4	ENST00000392492.8	NP_001079.1
AANAT	NM_001166579.2	c.217C>T	p.Arg73Trp	missense_variant	Exon 5 of 7		NP_001160051.1
AANAT	NR_110548.2	n.282C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AANAT	ENST00000392492.8	c.82C>T	p.Arg28Trp	missense_variant	Exon 2 of 4	1	NM_001088.3	ENSP00000376282.2
AANAT	ENST00000250615.7	c.217C>T	p.Arg73Trp	missense_variant	Exon 5 of 7	1		ENSP00000250615.2
AANAT	ENST00000585649.1	c.196C>T	p.Arg66Trp	missense_variant	Exon 1 of 3	1		ENSP00000468717.1
AANAT	ENST00000587798.1	n.82C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000468239.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249912 AF XY: 0.00000739

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461182 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726922

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52790

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

African (AFR) AF: 0.0000724 AC: 3 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82C>T (p.R28W) 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 82, causing the arginine (R) at amino acid position 28 to be replaced by a tryptophan (W). 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	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Benign	0.22
Sift	Uncertain	0.012	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.87	.;P;.
Vest4		0.83
MVP		0.79
MPC		0.11
ClinPred		0.80	D
GERP RS		3.3
PromoterAI		-0.0038	Neutral
Varity_R		0.18
gMVP		0.72
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs373005685; hg19: chr17-74464910; COSMIC: COSV51685001; COSMIC: COSV51685001;