Genetic Variant PNMT:c.-278G>T (chr17-39667885-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000394246.1(PNMT):c.-278G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 146,222 control chromosomes in the GnomAD database, including 113 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 0.032 ( 113 hom., cov: 25)

Exomes 𝑓: 0.0069 ( 0 hom. )

Consequence

PNMT
ENST00000394246.1 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.145

Publications

4 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NR_073461.2 link	n.-134G>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000394246.1 link	c.-278G>T		upstream_gene_variant		2		ENSP00000377791.1		A8MT87

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4682

AN:

145966

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0459

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.00645

Gnomad EAS

AF:

0.000667

Gnomad SAS

AF:

0.00379

Gnomad FIN

AF:

0.0396

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.0517

Gnomad OTH

AF:

0.0257

GnomAD4 exome

AF:

0.00694

AC:

AN:

144

Hom.:

AF XY:

0.00943

AC XY:

AN XY:

106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00877

AC:

AN:

114

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0321

AC:

4684

AN:

146078

Hom.:

113

Cov.:

AF XY:

0.0297

AC XY:

2119

AN XY:

71238

show subpopulations

African (AFR)

AF:

0.0118

AC:

477

AN:

40290

American (AMR)

AF:

0.0186

AC:

275

AN:

14800

Ashkenazi Jewish (ASJ)

AF:

0.00645

AC:

AN:

3412

East Asian (EAS)

AF:

0.000668

AC:

AN:

4488

South Asian (SAS)

AF:

0.00378

AC:

AN:

4234

European-Finnish (FIN)

AF:

0.0396

AC:

377

AN:

9530

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0517

AC:

3418

AN:

66116

Other (OTH)

AF:

0.0254

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

194

388

583

777

971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0375

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.3

(source)

DANN

Benign

0.91

PhyloP100

-0.14

PromoterAI

0.015

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over