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rs769224

chr22-19964281-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_000754.4(COMT):c.597G>A(p.Pro199=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,613,964 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.043 ( 219 hom., cov: 33)
Exomes 𝑓: 0.025 ( 580 hom. )

Consequence

COMT
NM_000754.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: -1.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 22-19964281-G-A is Benign according to our data. Variant chr22-19964281-G-A is described in ClinVar as [Benign]. Clinvar id is 828956.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-19964281-G-A is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.92 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COMTNM_000754.4 linkuse as main transcriptc.597G>A p.Pro199= synonymous_variant 5/6 ENST00000361682.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COMTENST00000361682.11 linkuse as main transcriptc.597G>A p.Pro199= synonymous_variant 5/61 NM_000754.4 P2P21964-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0432
AC:
6579
AN:
152172
Hom.:
219
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0934
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0288
Gnomad ASJ
AF:
0.0208
Gnomad EAS
AF:
0.0644
Gnomad SAS
AF:
0.0205
Gnomad FIN
AF:
0.0203
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0218
Gnomad OTH
AF:
0.0297
GnomAD3 exomes
AF:
0.0302
AC:
7592
AN:
251326
Hom.:
160
AF XY:
0.0282
AC XY:
3826
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.0924
Gnomad AMR exome
AF:
0.0267
Gnomad ASJ exome
AF:
0.0205
Gnomad EAS exome
AF:
0.0696
Gnomad SAS exome
AF:
0.0210
Gnomad FIN exome
AF:
0.0198
Gnomad NFE exome
AF:
0.0217
Gnomad OTH exome
AF:
0.0231
GnomAD4 exome
AF:
0.0245
AC:
35875
AN:
1461674
Hom.:
580
Cov.:
33
AF XY:
0.0242
AC XY:
17580
AN XY:
727154
show subpopulations
Gnomad4 AFR exome
AF:
0.0934
Gnomad4 AMR exome
AF:
0.0258
Gnomad4 ASJ exome
AF:
0.0215
Gnomad4 EAS exome
AF:
0.0533
Gnomad4 SAS exome
AF:
0.0219
Gnomad4 FIN exome
AF:
0.0172
Gnomad4 NFE exome
AF:
0.0219
Gnomad4 OTH exome
AF:
0.0276
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0433
AC:
6589
AN:
152290
Hom.:
219
Cov.:
33
AF XY:
0.0431
AC XY:
3207
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.0933
Gnomad4 AMR
AF:
0.0289
Gnomad4 ASJ
AF:
0.0208
Gnomad4 EAS
AF:
0.0645
Gnomad4 SAS
AF:
0.0205
Gnomad4 FIN
AF:
0.0203
Gnomad4 NFE
AF:
0.0218
Gnomad4 OTH
AF:
0.0294
Alfa
AF:
0.0258
Hom.:
150
Bravo
AF:
0.0462
Asia WGS
AF:
0.0380
AC:
134
AN:
3478
EpiCase
AF:
0.0215
EpiControl
AF:
0.0223

ClinVar

Significance: Benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 05, 2021- -
Tramadol response Other:1
drug response, no assertion criteria providedresearchBruce Budowle Laboratory, University of North Texas Health Science CenterApr 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_noAF
Benign
-0.84
Cadd
Benign
2.3
Dann
Benign
0.78
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769224; hg19: chr22-19951804; COSMIC: COSV52889936; COSMIC: COSV52889936; API