ENST00000394246.1:c.-93+222G>A

Variant names:

• chr17-39668292-G-A
• rs876493
• ENST00000394246.1:c.-93+222G>A

Variant summary

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

The ENST00000394246.1(PNMT):​c.-93+222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 466,844 control chromosomes in the GnomAD database, including 67,211 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 0.47 (18183 hom., cov: 30)
  • Exomes 𝑓: 0.55 (49028 hom.)
• Consequence: PNMT ENST00000394246.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 44 publications found

Genes affected

PNMT (HGNC:9160): (phenylethanolamine N-methyltransferase) The product of this gene catalyzes the last step of the catecholamine biosynthesis pathway, which methylates norepinephrine to form epinephrine (adrenaline). The enzyme also has beta-carboline 2N-methyltransferase activity. This gene is thought to play a key step in regulating epinephrine production. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394246.1. 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
	PNMT	NR_073461.2		n.52+222G>A		intron	N/A
	PNMT	NM_002686.4	MANE Select	c.-184G>A		upstream_gene	N/A	NP_002677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMT	ENST00000394246.1	TSL:2	c.-93+222G>A		intron	N/A	ENSP00000377791.1
	PNMT	ENST00000269582.3	TSL:1 MANE Select	c.-184G>A		upstream_gene	N/A	ENSP00000269582.2
	PNMT	ENST00000581428.1	TSL:2	c.-184G>A		upstream_gene	N/A	ENSP00000464234.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71636 AN: 151572 Hom.: 18186 Cov.: 30

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.466

GnomAD4 exome AF: 0.552 AC: 173977 AN: 315164 Hom.: 49028 Cov.: 4 AF XY: 0.554 AC XY: 90052 AN XY: 162444

African (AFR) AF: 0.311 AC: 2288 AN: 7354

American (AMR) AF: 0.365 AC: 2632 AN: 7218

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 5725 AN: 9896

East Asian (EAS) AF: 0.388 AC: 8603 AN: 22156

South Asian (SAS) AF: 0.613 AC: 9658 AN: 15746

European-Finnish (FIN) AF: 0.636 AC: 15852 AN: 24932

Middle Eastern (MID) AF: 0.563 AC: 853 AN: 1516

European-Non Finnish (NFE) AF: 0.571 AC: 118162 AN: 206922

Other (OTH) AF: 0.525 AC: 10204 AN: 19424

GnomAD4 genome AF: 0.472 AC: 71645 AN: 151680 Hom.: 18183 Cov.: 30 AF XY: 0.474 AC XY: 35126 AN XY: 74110

African (AFR) AF: 0.305 AC: 12609 AN: 41342

American (AMR) AF: 0.400 AC: 6109 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1615 AN: 5094

South Asian (SAS) AF: 0.567 AC: 2729 AN: 4816

European-Finnish (FIN) AF: 0.647 AC: 6819 AN: 10540

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.562 AC: 38154 AN: 67838

Other (OTH) AF: 0.458 AC: 965 AN: 2106

Alfa AF: 0.532 Hom.: 65247

Bravo AF: 0.442

Asia WGS AF: 0.443 AC: 1534 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		-0.17
PromoterAI		-0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs876493; hg19: chr17-37824545;