Genetic Variant PNMT:p.Ala21Glu (chr17-39668537-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002686.4(PNMT):c.62C>A(p.Ala21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PNMT
NM_002686.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0960

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07500431).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002686.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMT	NM_002686.4	MANE Select	c.62C>A	p.Ala21Glu	missense	Exon 1 of 3	NP_002677.1	P11086
	PNMT	NR_073461.2		n.52+467C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNMT	ENST00000269582.3	TSL:1 MANE Select	c.62C>A	p.Ala21Glu	missense	Exon 1 of 3	ENSP00000269582.2	P11086
PNMT	ENST00000581428.1	TSL:2	c.62C>A	p.Ala21Glu	missense	Exon 1 of 2	ENSP00000464234.1	J3QRI3
PNMT	ENST00000394246.1	TSL:2	c.-93+467C>A		intron	N/A	ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1394266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688976

African (AFR)

AF:

0.00

AC:

AN:

31840

American (AMR)

AF:

0.00

AC:

AN:

37206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25132

East Asian (EAS)

AF:

0.00

AC:

AN:

36600

South Asian (SAS)

AF:

0.00

AC:

AN:

79774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4842

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084260

Other (OTH)

AF:

0.00

AC:

AN:

58060

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.076

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.54

M_CAP

Benign

0.027

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.46

PhyloP100

0.096

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.050

REVEL

Benign

0.043

Sift

Benign

0.11

Sift4G

Benign

0.34

Polyphen

0.0030

Vest4

0.081

MutPred

0.58

Loss of helix (P = 0.0167)

MVP

0.061

MPC

0.33

ClinPred

0.41

GERP RS

-4.9

PromoterAI

0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.73

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over