Genetic Variant ASMT:p.Asp287Glu (chrX-1636511-C-G) – ACMG Classification: Likely_benign (-4 pts)

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. 12/19 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

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: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASMT	NM_001171038.2 link	c.861C>G	p.Asp287Glu	missense_variant	Exon 8 of 9	ENST00000381241.9	NP_001164509.1	P46597-3A0A024RBT9
ASMT	NM_001416525.1 link	c.777C>G	p.Asp259Glu	missense_variant	Exon 7 of 8		NP_001403454.1
ASMT	NM_001171039.1 link	c.636C>G	p.Asp212Glu	missense_variant	Exon 6 of 7		NP_001164510.1	P46597-2X5D784

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASMT	ENST00000381241.9 link	c.861C>G	p.Asp287Glu	missense_variant	Exon 8 of 9	1	NM_001171038.2	ENSP00000370639.3		P46597-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

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:

AN:

251166

AF XY:

0.0000147

show subpopulations

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:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0000299

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:

8.99e-7

AC:

AN:

1111832

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41376

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.010

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0094

.;T;.;.

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.0056

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

0.096

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

D;D;N;D

REVEL

Benign

0.17

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.99

D;.;D;.

Vest4

0.35

MutPred

0.86

Gain of methylation at K289 (P = 0.0693);.;.;.;

MVP

0.61

MPC

0.12

ClinPred

0.21

GERP RS

1.1

PromoterAI

-0.063

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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X-1636511-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over