dbSNP rs4933063: ASMT:p.Asp287Glu (chrX-1636511-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001171038.2(ASMT):c.861C>A(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. 1 hem. )

Consequence

ASMT
NM_001171038.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0960

Publications

0 publications found

Variant links:

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]

ASMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASMT	NM_001171038.2	MANE Select	c.861C>A	p.Asp287Glu	missense	Exon 8 of 9	NP_001164509.1	P46597-3
ASMT	NM_001416525.1		c.777C>A	p.Asp259Glu	missense	Exon 7 of 8	NP_001403454.1	X5D2A4
ASMT	NM_001171039.1		c.636C>A	p.Asp212Glu	missense	Exon 6 of 7	NP_001164510.1	X5D784

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111832

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.0060

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0094

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.70

M_CAP

Benign

0.0056

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.096

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.17

Sift

Benign

0.14

Sift4G

Benign

0.20

Polyphen

0.99

Vest4

0.35

MutPred

0.86

Gain of methylation at K289 (P = 0.0693)

MVP

0.61

MPC

0.12

ClinPred

0.79

GERP RS

1.1

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.35

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over