rs3810595

Variant names:

• chr22-19962121-G-C
• rs3810595
• NM_000754.4:c.1-406G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.1-406G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 296,138 control chromosomes in the GnomAD database, including 21,536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (10869 hom., cov: 33)
  • Exomes 𝑓: 0.37 (10667 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.54
• Publications: 8 publications found

Genes affected

COMT (HGNC:2228): (catechol-O-methyltransferase) Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]

COMT Gene-Disease associations (from GenCC):

• paroxysmal dyskinesia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.1-406G>C		intron_variant	Intron 2 of 5	ENST00000361682.11	NP_000745.1
COMT	NM_001135161.2	c.1-406G>C		intron_variant	Intron 2 of 5		NP_001128633.1
COMT	NM_001135162.2	c.1-406G>C		intron_variant	Intron 2 of 5		NP_001128634.1
COMT	NM_001362828.2	c.-294-112G>C		intron_variant	Intron 2 of 5		NP_001349757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.1-406G>C		intron_variant	Intron 2 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57257 AN: 151970 Hom.: 10865 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.423

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.374 AC: 53893 AN: 144048 Hom.: 10667 AF XY: 0.374 AC XY: 28542 AN XY: 76410

African (AFR) AF: 0.364 AC: 1786 AN: 4908

American (AMR) AF: 0.276 AC: 1970 AN: 7144

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1620 AN: 3606

East Asian (EAS) AF: 0.322 AC: 2234 AN: 6932

South Asian (SAS) AF: 0.340 AC: 7951 AN: 23404

European-Finnish (FIN) AF: 0.332 AC: 2463 AN: 7428

Middle Eastern (MID) AF: 0.443 AC: 241 AN: 544

European-Non Finnish (NFE) AF: 0.397 AC: 32733 AN: 82478

Other (OTH) AF: 0.381 AC: 2895 AN: 7604

GnomAD4 genome AF: 0.377 AC: 57289 AN: 152090 Hom.: 10869 Cov.: 33 AF XY: 0.372 AC XY: 27650 AN XY: 74360

African (AFR) AF: 0.375 AC: 15573 AN: 41478

American (AMR) AF: 0.330 AC: 5054 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1645 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1669 AN: 5158

South Asian (SAS) AF: 0.329 AC: 1589 AN: 4824

European-Finnish (FIN) AF: 0.309 AC: 3276 AN: 10586

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.401 AC: 27243 AN: 67968

Other (OTH) AF: 0.396 AC: 837 AN: 2116

Alfa AF: 0.380 Hom.: 1353

Bravo AF: 0.377

Asia WGS AF: 0.327 AC: 1140 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.96
DANN	Benign	0.44
PhyloP100		-4.5
PromoterAI		0.0038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3810595; hg19: chr22-19949644;