NM_001171038.2:c.568T>C

Variant names:

• chrX-1632709-T-C
• rs6588809
• NM_001171038.2:c.568T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001171038.2(ASMT):​c.568T>C​(p.Trp190Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 243,960 control chromosomes in the GnomAD database, including 23,649 homozygotes. There are 54,447 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.44 (14465 hom., 32666 hem., cov: 32)
  • Exomes 𝑓: 0.44 (9184 hom. 21781 hem.)
• Consequence: ASMT NM_001171038.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.109
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9969217E-5).
• BP6: Variant X-1632709-T-C is Benign according to our data. Variant chrX-1632709-T-C is described in ClinVar as [Benign]. Clinvar id is 3036492.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASMT	NM_001171038.2	c.568T>C	p.Trp190Arg	missense_variant	Exon 6 of 9	ENST00000381241.9	NP_001164509.1
ASMT	NM_001416525.1	c.563-441T>C		intron_variant	Intron 5 of 7		NP_001403454.1
ASMT	NM_001171039.1	c.562+2770T>C		intron_variant	Intron 5 of 6		NP_001164510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASMT	ENST00000381241.9	c.568T>C	p.Trp190Arg	missense_variant	Exon 6 of 9	1	NM_001171038.2	ENSP00000370639.3
ASMT	ENST00000381229.9	c.563-441T>C		intron_variant	Intron 5 of 7	1		ENSP00000370627.4
ASMT	ENST00000381233.8	c.562+2770T>C		intron_variant	Intron 5 of 6	1		ENSP00000370631.3
ASMT	ENST00000509780.6	n.289-3533T>C		intron_variant	Intron 1 of 1	1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67061 AN: 151634 Hom.: 14469 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.454 AC: 15436 AN: 33996 AF XY: 0.460

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.444 AC: 40944 AN: 92210 Hom.: 9184 Cov.: 0 AF XY: 0.452 AC XY: 21781 AN XY: 48232

African (AFR) AF: 0.424 AC: 1664 AN: 3922

American (AMR) AF: 0.408 AC: 1964 AN: 4812

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1242 AN: 2192

East Asian (EAS) AF: 0.452 AC: 2424 AN: 5358

South Asian (SAS) AF: 0.482 AC: 6126 AN: 12704

European-Finnish (FIN) AF: 0.356 AC: 1235 AN: 3468

Middle Eastern (MID) AF: 0.529 AC: 165 AN: 312

European-Non Finnish (NFE) AF: 0.438 AC: 23993 AN: 54722

Other (OTH) AF: 0.451 AC: 2131 AN: 4720

GnomAD4 genome AF: 0.442 AC: 67084 AN: 151750 Hom.: 14465 Cov.: 32 AF XY: 0.441 AC XY: 32666 AN XY: 74144

African (AFR) AF: 0.419 AC: 17340 AN: 41396

American (AMR) AF: 0.443 AC: 6725 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2006 AN: 3466

East Asian (EAS) AF: 0.466 AC: 2403 AN: 5156

South Asian (SAS) AF: 0.522 AC: 2509 AN: 4802

European-Finnish (FIN) AF: 0.345 AC: 3638 AN: 10552

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.455 AC: 30882 AN: 67880

Other (OTH) AF: 0.486 AC: 1021 AN: 2102

TwinsUK AF: 0.453 AC: 1680

ALSPAC AF: 0.456 AC: 1756

ExAC AF: 0.222 AC: 1510

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ASMT-related disorder Benign:1

Feb 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	-0.92	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	8.5
DANN	Benign	0.88
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.000020	T
MetaSVM	Benign	-0.74	T
PhyloP100		0.11
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.023
Sift	Benign	0.28	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.61		Gain of solvent accessibility (P = 0.0584);
MPC		0.025
ClinPred		0.0013	T

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6588809; hg19: chrX-1751602;