22-19964374-G-C

Position:

• chr22-19964374-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.615+75G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,604,012 control chromosomes in the GnomAD database, including 29,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2595 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26781 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.261

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045391023).
• BP6: Variant 22-19964374-G-C is Benign according to our data. Variant chr22-19964374-G-C is described in ClinVar as [Benign]. Clinvar id is 828955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+75G>C		intron_variant		ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.615+75G>C		intron_variant		1	NM_000754.4	ENSP00000354511	P2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27352 AN: 152112 Hom.: 2594 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.201 AC: 48457 AN: 240914 Hom.: 5030 AF XY: 0.201 AC XY: 26252 AN XY: 130566

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.188 AC: 273449 AN: 1451782 Hom.: 26781 Cov.: 30 AF XY: 0.190 AC XY: 137013 AN XY: 722302

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.243

Gnomad4 FIN exome AF: 0.297

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.180 AC: 27361 AN: 152230 Hom.: 2595 Cov.: 33 AF XY: 0.184 AC XY: 13656 AN XY: 74414

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.157

Alfa AF: 0.178 Hom.: 796

Bravo AF: 0.171

TwinsUK AF: 0.180 AC: 669

ALSPAC AF: 0.186 AC: 715

ExAC AF: 0.196 AC: 23739

Asia WGS AF: 0.168 AC: 587 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tramadol response Other:1

drug response, no assertion criteria provided

research

Bruce Budowle Laboratory, University of North Texas Health Science Center

Apr 28, 2018

- T:M1 = postmortem ratio or tramadol to O-desmethyltramadol; t-MP = model-based clustered metabolizer phenotype inferred from T:M1

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.95
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.080
Sift	Uncertain	0.017	D
Sift4G	Benign	0.078	T
Polyphen		0.0010	B
Vest4		0.021
MutPred		0.19		Loss of ubiquitination at K230 (P = 0.0011);
ClinPred		0.0032	T
GERP RS		-1.9

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: rs4646315; hg19: chr22-19951897; COSMIC: COSV52889132; COSMIC: COSV52889132;