NM_000754.4:c.*522G>C

Variant names:

• chr22-19969258-G-C
• rs165599
• NM_000754.4:c.*522G>C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000754.4(COMT):c.*522G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The gene COMT is a tumor suppressor gene (CancerMine: 3 TSG citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COMT NM_000754.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 233 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

ARVCF (HGNC:728): (ARVCF delta catenin family member) Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) is a member of the catenin family. This family plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the inside and outside environments of a cell. The ARVCF gene was isolated in the search for the genetic defect responsible for the autosomal dominant Velo-Cardio-Facial syndrome (VCFS), a relatively common human disorder with phenotypic features including cleft palate, conotruncal heart defects and facial dysmorphology. The ARVCF gene encodes a protein containing two motifs, a coiled coil domain in the N-terminus and a 10 armadillo repeat sequence in the midregion. Since these sequences can facilitate protein-protein interactions ARVCF is thought to function in a protein complex. In addition, ARVCF contains a predicted nuclear-targeting sequence suggesting that it may have a function as a nuclear protein. [provided by RefSeq, Jun 2010]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000754.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	COMT NM_000754.4	MANE Select	c.*522G>C	3_prime_UTR	Exon 6 of 6	Prot: NP_000745.1 UniProt:
	COMT NM_001135161.2		c.*522G>C	3_prime_UTR	Exon 6 of 6	Prot: NP_001128633.1 UniProt:
	COMT NM_001135162.2		c.*522G>C	3_prime_UTR	Exon 6 of 6	Prot: NP_001128634.1 UniProt:

COMT NM_000754.4

MANE Select

HGVSc / HGVSpc.*522G>C

Exon rankExon 6 of 6

3_prime_UTR

Prot: NP_000745.1UniProt: P21964-1A0A140VJG8

COMT NM_001135161.2

HGVSc / HGVSpc.*522G>C

Exon rankExon 6 of 6

3_prime_UTR

Prot: NP_001128633.1UniProt: P21964-1A0A140VJG8

COMT NM_001135162.2

HGVSc / HGVSpc.*522G>C

Exon rankExon 6 of 6

3_prime_UTR

Prot: NP_001128634.1UniProt: P21964-1A0A140VJG8

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	COMT ENST00000361682.11	TSL:1MANE Select	c.*522G>C	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000354511.6 UniProt:
	COMT ENST00000678769.1		c.*522G>C	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000503289.1 UniProt:
	COMT ENST00000852828.1		c.*522G>C	3_prime_UTR	Exon 7 of 7	Prot: ENSP00000522887.1 UniProt:

COMT ENST00000361682.11

TSL:1MANE Select

HGVSc / HGVSpc.*522G>C

Exon rankExon 6 of 6

3_prime_UTR

Prot: ENSP00000354511.6UniProt: P21964-1

COMT ENST00000678769.1

HGVSc / HGVSpc.*522G>C

Exon rankExon 7 of 7

3_prime_UTR

Prot: ENSP00000503289.1UniProt: A0A7I2V370

COMT ENST00000852828.1

HGVSc / HGVSpc.*522G>C

Exon rankExon 7 of 7

3_prime_UTR

Prot: ENSP00000522887.1UniProt: A0ACI8VGL7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:0
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.1
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.42
GPN-Star LLR	N/A	-0.59
GPN-Star score	N/A	0.59
PhyloP100	Benign	0.076

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs165599;

hg19: chr22-19956781;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar