X-1636511-C-G

Variant names:

• chrX-1636511-C-G
• rs4933063
• NM_001171038.2:c.861C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001171038.2(ASMT):​c.861C>G​(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D287D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., 2 hem., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom. 3 hem.)
• Consequence: ASMT NM_001171038.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• Publications: 0 publications found

Genes affected

ASMT (HGNC:750): (acetylserotonin O-methyltransferase) This gene belongs to the methyltransferase superfamily, and is located in the pseudoautosomal region (PAR) at the end of the short arms of the X and Y chromosomes. The encoded enzyme catalyzes the final reaction in the synthesis of melatonin, and is abundant in the pineal gland. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171038.2. 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
	ASMT	NM_001171038.2	MANE Select	c.861C>G	p.Asp287Glu	missense	Exon 8 of 9	NP_001164509.1	P46597-3
	ASMT	NM_001416525.1		c.777C>G	p.Asp259Glu	missense	Exon 7 of 8	NP_001403454.1	X5D2A4
	ASMT	NM_001171039.1		c.636C>G	p.Asp212Glu	missense	Exon 6 of 7	NP_001164510.1	X5D784

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASMT	ENST00000381241.9	TSL:1 MANE Select	c.861C>G	p.Asp287Glu	missense	Exon 8 of 9	ENSP00000370639.3	P46597-3
	ASMT	ENST00000381229.9	TSL:1	c.777C>G	p.Asp259Glu	missense	Exon 7 of 8	ENSP00000370627.4	P46597-1
	ASMT	ENST00000381233.8	TSL:1	c.636C>G	p.Asp212Glu	missense	Exon 6 of 7	ENSP00000370631.3	P46597-2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151996 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251166 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727134

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74246

African (AFR) AF: 0.000121 AC: 5 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.010
DANN	Benign	0.92
DEOGEN2	Benign	0.0094	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0056	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.096
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.35
MutPred		0.86		Gain of methylation at K289 (P = 0.0693)
MVP		0.61
MPC		0.12
ClinPred		0.21	T
GERP RS		1.1
PromoterAI		-0.063	Neutral
Varity_R		0.35
Mutation Taster		=83/17	polymorphism

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: rs4933063; hg19: chrX-1755404; COSMIC: COSV67110248; COSMIC: COSV67110248;