rs376443578

Variant names:

• chr17-76468831-C-A
• rs376443578
• NM_001088.3:c.85C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-76468831-C-A
• chr17-76468831-C-G
• chr17-76468831-C-T

Variant summary

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

The NM_001088.3(AANAT):​c.85C>A​(p.Arg29Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• Publications: 1 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.85C>A	p.Arg29Ser	missense_variant	Exon 2 of 4	ENST00000392492.8	NP_001079.1
AANAT	NM_001166579.2	c.220C>A	p.Arg74Ser	missense_variant	Exon 5 of 7		NP_001160051.1
AANAT	NR_110548.2	n.285C>A		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.85C>A	p.Arg29Ser	missense_variant	Exon 2 of 4	1	NM_001088.3	ENSP00000376282.2
AANAT	ENST00000250615.7	c.220C>A	p.Arg74Ser	missense_variant	Exon 5 of 7	1		ENSP00000250615.2
AANAT	ENST00000585649.1	c.199C>A	p.Arg67Ser	missense_variant	Exon 1 of 3	1		ENSP00000468717.1
AANAT	ENST00000587798.1	n.85C>A		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000468239.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.9	.;M;.
PhyloP100		5.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.047	D;T;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.30		.;Gain of glycosylation at R29 (P = 0.0505);.;
MVP		0.81
MPC		0.38
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.014	Neutral
Varity_R		0.35
gMVP		0.80

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: rs376443578; hg19: chr17-74464913;