X-1615250-C-A

Variant names:

• chrX-1615250-C-A
• rs17149149
• NM_001171038.2:c.51C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.865
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063019395).
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.51C>A	p.Asn17Lys	missense	Exon 1 of 9	NP_001164509.1	P46597-3
	ASMT	NM_001416525.1		c.51C>A	p.Asn17Lys	missense	Exon 1 of 8	NP_001403454.1	X5D2A4
	ASMT	NM_001171039.1		c.51C>A	p.Asn17Lys	missense	Exon 1 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.51C>A	p.Asn17Lys	missense	Exon 1 of 9	ENSP00000370639.3	P46597-3
	ASMT	ENST00000381229.9	TSL:1	c.51C>A	p.Asn17Lys	missense	Exon 1 of 8	ENSP00000370627.4	P46597-1
	ASMT	ENST00000381233.8	TSL:1	c.51C>A	p.Asn17Lys	missense	Exon 1 of 7	ENSP00000370631.3	P46597-2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152066 Hom.: 8 Cov.: 31

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

GnomAD2 exomes AF: 0.00680 AC: 1492 AN: 219496 AF XY: 0.00843

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 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

African (AFR) AF: 0.00232 AC: 77 AN: 33192

American (AMR) AF: 0.000670 AC: 28 AN: 41800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.0225 AC: 879 AN: 39034

South Asian (SAS) AF: 0.0382 AC: 3168 AN: 82990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52132

Middle Eastern (MID) AF: 0.00314 AC: 18 AN: 5736

European-Non Finnish (NFE) AF: 0.0000625 AC: 69 AN: 1103218

Other (OTH) AF: 0.00438 AC: 262 AN: 59760

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

African (AFR) AF: 0.00226 AC: 94 AN: 41556

American (AMR) AF: 0.000787 AC: 12 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0279 AC: 144 AN: 5166

South Asian (SAS) AF: 0.0386 AC: 186 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ASMT-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.86
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Benign	0.044	D
Sift4G	Uncertain	0.057	T
Polyphen		0.99	D
Vest4		0.23
MutPred		0.86		Gain of ubiquitination at N17 (P = 0.0388)
MVP		0.43
MPC		0.10
ClinPred		0.048	T
GERP RS		-2.3
PromoterAI		-0.036	Neutral
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

Other links and lift over

dbSNP: rs17149149; hg19: chrX-1734143; COSMIC: COSV107494727;