chr17-76469731-G-C

Variant names:

• chr17-76469731-G-C
• rs28936679
• NM_001088.3:c.385G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001088.3(AANAT):​c.385G>C​(p.Ala129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A129T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.654
• Publications: 13 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14043847).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001088.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AANAT	NM_001088.3	MANE Select	c.385G>C	p.Ala129Pro	missense	Exon 4 of 4	NP_001079.1	F1T0I5
	AANAT	NM_001166579.2		c.520G>C	p.Ala174Pro	missense	Exon 7 of 7	NP_001160051.1	Q16613-2
	AANAT	NR_110548.2		n.641G>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AANAT	ENST00000392492.8	TSL:1 MANE Select	c.385G>C	p.Ala129Pro	missense	Exon 4 of 4	ENSP00000376282.2	Q16613-1
	AANAT	ENST00000250615.7	TSL:1	c.520G>C	p.Ala174Pro	missense	Exon 7 of 7	ENSP00000250615.2	Q16613-2
	AANAT	ENST00000878873.1		c.385G>C	p.Ala129Pro	missense	Exon 4 of 4	ENSP00000548932.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.65
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.086
Sift	Benign	0.17	T
Sift4G	Benign	0.21	T
Polyphen		0.82	P
Vest4		0.16
MutPred		0.33		Loss of MoRF binding (P = 0.055)
MVP		0.14
MPC		0.073
ClinPred		0.97	D
GERP RS		-1.2
Varity_R		0.34
gMVP		0.73

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

Other links and lift over

dbSNP: rs28936679; hg19: chr17-74465813;