rs165895

Variant names:

• chr22-19965536-T-C
• rs165895
• NM_000754.4:c.615+1237T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-19965536-T-C
• chr22-19965536-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000754.4(COMT):​c.615+1237T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,908 control chromosomes in the GnomAD database, including 7,524 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 0.31 (7520 hom., cov: 32)
  • Exomes 𝑓: 0.56 (4 hom.)
• Consequence: COMT NM_000754.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.533
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMT	NM_000754.4	c.615+1237T>C		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.615+1237T>C		intron_variant	Intron 5 of 5	1	NM_000754.4	ENSP00000354511.6

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47159 AN: 151756 Hom.: 7518 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.298

GnomAD4 exome AF: 0.559 AC: 19 AN: 34 Hom.: 4 Cov.: 0 AF XY: 0.563 AC XY: 18 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.571 AC: 16 AN: 28

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.311 AC: 47162 AN: 151874 Hom.: 7520 Cov.: 32 AF XY: 0.308 AC XY: 22888 AN XY: 74194

African (AFR) AF: 0.255 AC: 10575 AN: 41414

American (AMR) AF: 0.275 AC: 4198 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1205 AN: 3464

East Asian (EAS) AF: 0.244 AC: 1259 AN: 5158

South Asian (SAS) AF: 0.255 AC: 1229 AN: 4812

European-Finnish (FIN) AF: 0.368 AC: 3877 AN: 10534

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23706 AN: 67916

Other (OTH) AF: 0.296 AC: 624 AN: 2110

Alfa AF: 0.318 Hom.: 977

Bravo AF: 0.302

Asia WGS AF: 0.258 AC: 897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.29
PhyloP100		0.53
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: rs165895; hg19: chr22-19953059;