NM_001088.3:c.391C>T

Variant names:

• chr17-76469737-C-T
• rs970708682
• NM_001088.3:c.391C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001088.3(AANAT):​c.391C>T​(p.Arg131Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000519 in 1,559,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

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.391C>T	p.Arg131Trp	missense	Exon 4 of 4	NP_001079.1	F1T0I5
	AANAT	NM_001166579.2		c.526C>T	p.Arg176Trp	missense	Exon 7 of 7	NP_001160051.1	Q16613-2
	AANAT	NR_110548.2		n.647C>T		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.391C>T	p.Arg131Trp	missense	Exon 4 of 4	ENSP00000376282.2	Q16613-1
	AANAT	ENST00000250615.7	TSL:1	c.526C>T	p.Arg176Trp	missense	Exon 7 of 7	ENSP00000250615.2	Q16613-2
	AANAT	ENST00000878873.1		c.391C>T	p.Arg131Trp	missense	Exon 4 of 4	ENSP00000548932.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000220 AC: 4 AN: 181882 AF XY: 0.0000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000509

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 77 AN: 1407030 Hom.: 0 Cov.: 31 AF XY: 0.0000533 AC XY: 37 AN XY: 694040

African (AFR) AF: 0.0000309 AC: 1 AN: 32332

American (AMR) AF: 0.00 AC: 0 AN: 38196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23962

East Asian (EAS) AF: 0.00 AC: 0 AN: 37930

South Asian (SAS) AF: 0.00 AC: 0 AN: 79500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5158

European-Non Finnish (NFE) AF: 0.0000692 AC: 75 AN: 1083720

Other (OTH) AF: 0.0000173 AC: 1 AN: 57880

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000784 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.55
Sift	Benign	0.047	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.65
MPC		0.37
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.77
gMVP		0.87
Mutation Taster		=34/66	disease causing

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: rs970708682; hg19: chr17-74465819; COSMIC: COSV51684323; COSMIC: COSV51684323;