rs8192488

Variant names:

• chr22-19963714-C-T
• rs8192488
• NM_000754.4:c.438C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000754.4(COMT):​c.438C>T​(p.Ala146Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,612,932 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (168 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (158 hom.)
• Consequence: COMT NM_000754.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.76
• Publications: 12 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]

MIR4761 (HGNC:41591): (microRNA 4761) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.008).
• BP6: Variant 22-19963714-C-T is Benign according to our data. Variant chr22-19963714-C-T is described in ClinVar as Benign. ClinVar VariationId is 790230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.082 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.438C>T	p.Ala146Ala	synonymous_variant	Exon 4 of 6	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.438C>T	p.Ala146Ala	synonymous_variant	Exon 4 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3762 AN: 152168 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00673 AC: 1683 AN: 250082 AF XY: 0.00480

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00281 AC: 4104 AN: 1460646 Hom.: 158 Cov.: 36 AF XY: 0.00246 AC XY: 1791 AN XY: 726652

African (AFR) AF: 0.0911 AC: 3051 AN: 33478

American (AMR) AF: 0.00593 AC: 265 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86252

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52250

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000308 AC: 342 AN: 1111974

Other (OTH) AF: 0.00629 AC: 380 AN: 60378

GnomAD4 genome AF: 0.0248 AC: 3772 AN: 152286 Hom.: 168 Cov.: 33 AF XY: 0.0232 AC XY: 1730 AN XY: 74454

African (AFR) AF: 0.0844 AC: 3505 AN: 41538

American (AMR) AF: 0.0110 AC: 169 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68022

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.00947 Hom.: 63

Bravo AF: 0.0293

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

COMT-related disorder Benign:1

Mar 12, 2019

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_noAF	Benign	-0.72
CADD	Benign	0.34
DANN	Benign	0.72
PhyloP100		-1.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
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: rs8192488; hg19: chr22-19951237;