chr22-19961219-C-G

Variant names:

• chr22-19961219-C-G
• rs11569715
• NM_000754.4:c.-71C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000754.4(COMT):​c.-71C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 152,356 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0073 (20 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COMT NM_000754.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00731 (1114/152356) while in subpopulation AFR AF = 0.0252 (1047/41574). AF 95% confidence interval is 0.0239. There are 20 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1114 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	NM_000754.4	MANE Select	c.-71C>G		5_prime_UTR	Exon 2 of 6	NP_000745.1
	COMT	NM_001135161.2		c.-71C>G		5_prime_UTR	Exon 2 of 6	NP_001128633.1
	COMT	NM_001135162.2		c.-71C>G		5_prime_UTR	Exon 2 of 6	NP_001128634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMT	ENST00000361682.11	TSL:1 MANE Select	c.-71C>G		5_prime_UTR	Exon 2 of 6	ENSP00000354511.6
	COMT	ENST00000406520.7	TSL:1	c.-71C>G		5_prime_UTR	Exon 2 of 6	ENSP00000385150.3
	COMT	ENST00000964897.1		c.-71C>G		5_prime_UTR	Exon 2 of 6	ENSP00000634956.1

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 1105 AN: 152238 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00573

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 56 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00731 AC: 1114 AN: 152356 Hom.: 20 Cov.: 34 AF XY: 0.00717 AC XY: 534 AN XY: 74514

African (AFR) AF: 0.0252 AC: 1047 AN: 41574

American (AMR) AF: 0.00274 AC: 42 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68028

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00169 Hom.: 4

Bravo AF: 0.00833

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.7
DANN	Benign	0.79
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	polymorphism

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: rs11569715; hg19: chr22-19948742;