rs3788319

Variant names:

• chr22-19942028-A-G
• rs3788319
• NM_000754.4:c.-92+131A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000754.4(COMT):​c.-92+131A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 383,990 control chromosomes in the GnomAD database, including 50,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20442 hom., cov: 30)
  • Exomes 𝑓: 0.50 (29753 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.47
• Publications: 17 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]

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-19942028-A-G is Benign according to our data. Variant chr22-19942028-A-G is described in ClinVar as Benign. ClinVar VariationId is 678640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.-92+131A>G		intron_variant	Intron 1 of 5	ENST00000361682.11	NP_000745.1
TXNRD2	NM_006440.5	c.-225T>C		upstream_gene_variant		ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.-92+131A>G		intron_variant	Intron 1 of 5	1	NM_000754.4	ENSP00000354511.6
TXNRD2	ENST00000400521.7	c.-225T>C		upstream_gene_variant		1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 77847 AN: 151122 Hom.: 20416 Cov.: 30

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.503 AC: 117020 AN: 232756 Hom.: 29753 Cov.: 4 AF XY: 0.506 AC XY: 61008 AN XY: 120590

African (AFR) AF: 0.568 AC: 3056 AN: 5376

American (AMR) AF: 0.430 AC: 2232 AN: 5192

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 4980 AN: 7496

East Asian (EAS) AF: 0.381 AC: 6352 AN: 16672

South Asian (SAS) AF: 0.510 AC: 6763 AN: 13252

European-Finnish (FIN) AF: 0.387 AC: 7232 AN: 18670

Middle Eastern (MID) AF: 0.559 AC: 608 AN: 1088

European-Non Finnish (NFE) AF: 0.520 AC: 78179 AN: 150344

Other (OTH) AF: 0.519 AC: 7618 AN: 14666

GnomAD4 genome AF: 0.515 AC: 77914 AN: 151234 Hom.: 20442 Cov.: 30 AF XY: 0.509 AC XY: 37583 AN XY: 73856

African (AFR) AF: 0.575 AC: 23703 AN: 41210

American (AMR) AF: 0.473 AC: 7193 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2335 AN: 3470

East Asian (EAS) AF: 0.386 AC: 1967 AN: 5090

South Asian (SAS) AF: 0.508 AC: 2438 AN: 4800

European-Finnish (FIN) AF: 0.364 AC: 3776 AN: 10386

Middle Eastern (MID) AF: 0.548 AC: 160 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34743 AN: 67766

Other (OTH) AF: 0.552 AC: 1165 AN: 2110

Alfa AF: 0.511 Hom.: 2951

Bravo AF: 0.522

Asia WGS AF: 0.443 AC: 1542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-2.5
PromoterAI		-0.18	Neutral
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: rs3788319; hg19: chr22-19929551; COSMIC: COSV57634808; COSMIC: COSV57634808;