17-76469729-G-C

Variant names:

• chr17-76469729-G-C
• rs150357567
• NM_001088.3:c.383G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001088.3(AANAT):​c.383G>C​(p.Arg128Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,401,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 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.383G>C	p.Arg128Pro	missense_variant	Exon 4 of 4	ENST00000392492.8	NP_001079.1
AANAT	NM_001166579.2	c.518G>C	p.Arg173Pro	missense_variant	Exon 7 of 7		NP_001160051.1
AANAT	NR_110548.2	n.639G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AANAT	ENST00000392492.8	c.383G>C	p.Arg128Pro	missense_variant	Exon 4 of 4	1	NM_001088.3	ENSP00000376282.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1401202 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000555

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.33	.;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.30	.;B
Vest4		0.59
MutPred		0.59		.;Loss of MoRF binding (P = 6e-04);
MVP		0.16
MPC		0.34
ClinPred		0.63	D
GERP RS		-4.1
Varity_R		0.28
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150357567; hg19: chr17-74465811;