rs139765369

Variant names:

• chr17-76468838-C-G
• NM_001088.3:c.92C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-76468838-C-G
• chr17-76468838-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001088.3(AANAT):​c.92C>G​(p.Thr31Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AANAT NM_001088.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34

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 4 ACMG points.

• PM1: In a modified_residue Phosphothreonine; by PKA (size 0) in uniprot entity SNAT_HUMAN
• 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.92C>G	p.Thr31Arg	missense_variant	Exon 2 of 4	ENST00000392492.8	NP_001079.1
AANAT	NM_001166579.2	c.227C>G	p.Thr76Arg	missense_variant	Exon 5 of 7		NP_001160051.1
AANAT	NR_110548.2	n.292C>G		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.92C>G	p.Thr31Arg	missense_variant	Exon 2 of 4	1	NM_001088.3	ENSP00000376282.2
AANAT	ENST00000250615.7	c.227C>G	p.Thr76Arg	missense_variant	Exon 5 of 7	1		ENSP00000250615.2
AANAT	ENST00000585649.1	c.206C>G	p.Thr69Arg	missense_variant	Exon 1 of 3	1		ENSP00000468717.1
AANAT	ENST00000587798.1	n.92C>G		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000468239.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461258 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726976

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: 8.99e-7

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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	0.022	D
MutationAssessor	Uncertain	2.9	.;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.85
MutPred		0.23		.;Loss of phosphorylation at T31 (P = 0.0073);.;
MVP		0.84
MPC		0.39
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.59
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-74464920;