NM_000754.4:c.616-902G>A

Variant names:

• chr22-19967634-G-A
• rs9306235
• NM_000754.4:c.616-902G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000754.4(COMT):​c.616-902G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 310,602 control chromosomes in the GnomAD database, including 536 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 0.049 (238 hom., cov: 33)
  • Exomes 𝑓: 0.053 (298 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.800
• Publications: 6 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]

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.616-902G>A		intron_variant	Intron 5 of 5	ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMT	ENST00000361682.11	c.616-902G>A		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7421 AN: 152130 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.0626

GnomAD4 exome AF: 0.0533 AC: 8448 AN: 158354 Hom.: 298 Cov.: 0 AF XY: 0.0489 AC XY: 4233 AN XY: 86482

African (AFR) AF: 0.0126 AC: 51 AN: 4042

American (AMR) AF: 0.0462 AC: 299 AN: 6466

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 251 AN: 3716

East Asian (EAS) AF: 0.00 AC: 0 AN: 5972

South Asian (SAS) AF: 0.0144 AC: 471 AN: 32696

European-Finnish (FIN) AF: 0.0534 AC: 392 AN: 7346

Middle Eastern (MID) AF: 0.0556 AC: 34 AN: 612

European-Non Finnish (NFE) AF: 0.0725 AC: 6521 AN: 89902

Other (OTH) AF: 0.0564 AC: 429 AN: 7602

GnomAD4 genome AF: 0.0488 AC: 7424 AN: 152248 Hom.: 238 Cov.: 33 AF XY: 0.0474 AC XY: 3525 AN XY: 74430

African (AFR) AF: 0.0132 AC: 549 AN: 41546

American (AMR) AF: 0.0608 AC: 930 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 259 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4822

European-Finnish (FIN) AF: 0.0483 AC: 513 AN: 10618

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0715 AC: 4864 AN: 68006

Other (OTH) AF: 0.0620 AC: 131 AN: 2114

Alfa AF: 0.0685 Hom.: 491

Bravo AF: 0.0497

Asia WGS AF: 0.00780 AC: 28 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.56
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -4

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

Other links and lift over

dbSNP: rs9306235; hg19: chr22-19955157;