X-1629941-T-C

Position:

• chrX-1629941-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001171038.2(ASMT):​c.562+2T>C variant causes a splice donor change. The variant allele was found at a frequency of 0.00174 in 1,611,446 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,376 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 131 hem., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom. 1245 hem.)
• Consequence: ASMT NM_001171038.2 splice_donor
• Scores: Splicing: ADA: 0.9068
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 5.68

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.43954).
• BS2: High Hemizygotes in GnomAd4 at 131 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASMT	NM_001171038.2	c.562+2T>C		splice_donor_variant		ENST00000381241.9
ASMT	NM_001171039.1	c.562+2T>C		splice_donor_variant
ASMT	NM_001416525.1	c.562+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASMT	ENST00000381241.9	c.562+2T>C		splice_donor_variant		1	NM_001171038.2
ASMT	ENST00000381229.9	c.562+2T>C		splice_donor_variant		1		P1
ASMT	ENST00000381233.8	c.562+2T>C		splice_donor_variant		1
ASMT	ENST00000509780.6	n.288+1908T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74348

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251180 Hom.: 1 AF XY: 0.00134 AC XY: 182 AN XY: 135744

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00173 AC: 2519 AN: 1459150 Hom.: 7 Cov.: 31 AF XY: 0.00171 AC XY: 1245 AN XY: 725978

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74476

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00127

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00138 AC: 168

EpiCase AF: 0.00207

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ASMT: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.44
FATHMM_MKL	Benign	0.71	D
MutationTaster	Benign	1.0	N;N;N
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: 29
DS_DL_spliceai		0.72		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148855515; hg19: chrX-1748834;