chr22-19965536-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.533
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons MANE Protein UniProt
COMTNM_000754.4 linkuse as main transcriptc.615+1237T>C intron_variant ENST00000361682.11 NP_000745.1 P21964-1A0A140VJG8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COMTENST00000361682.11 linkuse as main transcriptc.615+1237T>C intron_variant 1 NM_000754.4 ENSP00000354511.6 P21964-1

Frequencies

GnomAD3 genomes
AF:
0.311
AC:
47159
AN:
151756
Hom.:
7518
Cov.:
32
show subpopulations
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
show subpopulations
Gnomad4 SAS exome
AF:
0.500
Gnomad4 NFE exome
AF:
0.571
Gnomad4 OTH exome
AF:
0.500
GnomAD4 genome
AF:
0.311
AC:
47162
AN:
151874
Hom.:
7520
Cov.:
32
AF XY:
0.308
AC XY:
22888
AN XY:
74194
show subpopulations
Gnomad4 AFR
AF:
0.255
Gnomad4 AMR
AF:
0.275
Gnomad4 ASJ
AF:
0.348
Gnomad4 EAS
AF:
0.244
Gnomad4 SAS
AF:
0.255
Gnomad4 FIN
AF:
0.368
Gnomad4 NFE
AF:
0.349
Gnomad4 OTH
AF:
0.296
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

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: rs165895; hg19: chr22-19953059; API