dbSNP rs876493: PNMT:c.-93+222G>A (chr17-39668292-G-A) – 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.-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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.175

Publications

44 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:

Genome browser will be placed here

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=-0.67).

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 rank	MANE	Protein	UniProt
PNMT	NR_073461.2 link	n.52+222G>A		intron_variant	Intron 1 of 2
PNMT	NM_002686.4 link	c.-184G>A		upstream_gene_variant		ENST00000269582.3	NP_002677.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PNMT	ENST00000394246.1 link	c.-93+222G>A	intron_variant	Intron 1 of 2	2		ENSP00000377791.1
PNMT	ENST00000269582.3 link	c.-184G>A	upstream_gene_variant		1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000581428.1 link	c.-184G>A	upstream_gene_variant		2		ENSP00000464234.1

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71636

AN:

151572

Hom.:

18186

Cov.:

show subpopulations

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.:

AF XY:

0.554

AC XY:

90052

AN XY:

162444

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

3842

7683

11525

15366

19208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

812

1624

2436

3248

4060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.472

AC:

71645

AN:

151680

Hom.:

18183

Cov.:

AF XY:

0.474

AC XY:

35126

AN XY:

74110

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1756

3512

5269

7025

8781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.532

Hom.:

65247

Bravo

AF:

0.442

Asia WGS

AF:

0.443

AC:

1534

AN:

3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.17

PromoterAI

-0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over