NM_000754.4:c.480C>G

Variant names:

• chr22-19963756-C-G
• rs1601529589
• NM_000754.4:c.480C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000754.4(COMT):​c.480C>G​(p.Asp160Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COMT NM_000754.4 missense
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.278

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33496627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.480C>G	p.Asp160Glu	missense_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.480C>G	p.Asp160Glu	missense_variant	Exon 4 of 6	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Tramadol response Other:1

Apr 28, 2018

Bruce Budowle Laboratory, University of North Texas Health Science Center

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T;T;T;T;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.72	.;T;.;.;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;.;L;L;.;L;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.1	N;N;N;.;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.097	T;T;T;.;D;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;.;B;.
Vest4		0.24
MutPred		0.56		Loss of catalytic residue at K159 (P = 0.1122);Loss of catalytic residue at K159 (P = 0.1122);Loss of catalytic residue at K159 (P = 0.1122);Loss of catalytic residue at K159 (P = 0.1122);Loss of catalytic residue at K159 (P = 0.1122);Loss of catalytic residue at K159 (P = 0.1122);.;
MVP		0.76
MPC		0.25
ClinPred		0.38	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.46

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: rs1601529589; hg19: chr22-19951279;