rs876493

Positions:

• chr17-39668292-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNMT	NR_073461.2	n.52+222G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000394246.1	c.-93+222G>A		intron_variant		2		ENSP00000377791

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

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.579

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.613

Gnomad4 FIN exome AF: 0.636

Gnomad4 NFE exome AF: 0.571

Gnomad4 OTH exome AF: 0.525

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

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.647

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.458

Alfa AF: 0.540 Hom.: 25934

Bravo AF: 0.442

Asia WGS AF: 0.443 AC: 1534 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Other links and lift over

dbSNP: rs876493; hg19: chr17-37824545;