17-76469731-G-T

Variant names:

• chr17-76469731-G-T
• NM_001088.3:c.385G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001088.3(AANAT):​c.385G>T​(p.Ala129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 7.1e-7 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.654

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0388138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AANAT	NM_001088.3	c.385G>T	p.Ala129Ser	missense_variant	Exon 4 of 4	ENST00000392492.8	NP_001079.1
AANAT	NM_001166579.2	c.520G>T	p.Ala174Ser	missense_variant	Exon 7 of 7		NP_001160051.1
AANAT	NR_110548.2	n.641G>T		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.385G>T	p.Ala129Ser	missense_variant	Exon 4 of 4	1	NM_001088.3	ENSP00000376282.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404360 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692242

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: 0.0000208

Gnomad4 NFE exome AF: 0.00

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	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.75
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.91	.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.56	N;N
REVEL	Benign	0.010
Sift	Benign	0.60	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.013	.;B
Vest4		0.060
MutPred		0.18		.;Gain of disorder (P = 0.0977);
MVP		0.072
MPC		0.059
ClinPred		0.034	T
GERP RS		-1.2
Varity_R		0.059
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-74465813;