Genetic Variant PNMT:c.-93+16G>C (chr17-39668086-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000394246.1(PNMT):c.-93+16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. 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: not found (cov: 20)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

PNMT
ENST00000394246.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.697

Publications

0 publications found

Variant links:

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]

PNMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NR_073461.2 link	n.52+16G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000394246.1 link	c.-93+16G>C		intron_variant	Intron 1 of 2	2		ENSP00000377791.1		A8MT87

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000575

AC:

AN:

34770

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

17346

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

1502

American (AMR)

AF:

0.00

AC:

AN:

864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1522

East Asian (EAS)

AF:

0.00

AC:

AN:

2714

South Asian (SAS)

AF:

0.00

AC:

AN:

480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0000862

AC:

AN:

23198

Other (OTH)

AF:

0.00

AC:

AN:

2436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.5

(source)

DANN

Benign

0.57

PhyloP100

-0.70

PromoterAI

0.048

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over