rs17149149

Positions:

• chrX-1615250-C-A
• chrX-1615250-C-G
• chrX-1615250-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001171038.2(ASMT):​c.51C>A​(p.Asn17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,595,758 control chromosomes in the GnomAD database, including 126 homozygotes. There are 3,268 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0030 (8 hom., 273 hem., cov: 31)
  • Exomes 𝑓: 0.0031 (118 hom. 2995 hem.)
• Consequence: ASMT NM_001171038.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.865

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063019395).
• BP6: Variant X-1615250-C-A is Benign according to our data. Variant chrX-1615250-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2688614.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00298 (453/152184) while in subpopulation SAS AF= 0.0386 (186/4824). AF 95% confidence interval is 0.034. There are 8 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASMT	NM_001171038.2	c.51C>A	p.Asn17Lys	missense_variant	1/9	ENST00000381241.9
ASMT	NM_001416525.1	c.51C>A	p.Asn17Lys	missense_variant	1/8
ASMT	NM_001171039.1	c.51C>A	p.Asn17Lys	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASMT	ENST00000381241.9	c.51C>A	p.Asn17Lys	missense_variant	1/9	1	NM_001171038.2
ASMT	ENST00000381229.9	c.51C>A	p.Asn17Lys	missense_variant	1/8	1		P1
ASMT	ENST00000381233.8	c.51C>A	p.Asn17Lys	missense_variant	1/7	1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152066 Hom.: 8 Cov.: 31 AF XY: 0.00362 AC XY: 269 AN XY: 74264

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0278

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00680 AC: 1492 AN: 219496 Hom.: 37 AF XY: 0.00843 AC XY: 995 AN XY: 118066

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.000739

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0279

Gnomad SAS exome AF: 0.0353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00312 AC: 4501 AN: 1443574 Hom.: 118 Cov.: 32 AF XY: 0.00418 AC XY: 2995 AN XY: 716094

Gnomad4 AFR exome AF: 0.00232

Gnomad4 AMR exome AF: 0.000670

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0382

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000625

Gnomad4 OTH exome AF: 0.00438

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152184 Hom.: 8 Cov.: 31 AF XY: 0.00367 AC XY: 273 AN XY: 74392

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.000787

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0279

Gnomad4 SAS AF: 0.0386

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00520

Bravo AF: 0.00242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00652 AC: 789

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 13, 2023

- -

ASMT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.97
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.14
Sift	Benign	0.044	D;T;T
Sift4G	Uncertain	0.057	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.23
MutPred		0.86		Gain of ubiquitination at N17 (P = 0.0388);Gain of ubiquitination at N17 (P = 0.0388);Gain of ubiquitination at N17 (P = 0.0388);
MVP		0.43
MPC		0.10
ClinPred		0.048	T
GERP RS		-2.3
Varity_R		0.32

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

LitVar

Other links and lift over

dbSNP: rs17149149; hg19: chrX-1734143;