Variant 17-39668609-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002686.4(PNMT):c.134G>C(p.Gly45Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,453,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000034 ( 0 hom. )

Consequence

PNMT
NM_002686.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

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:

PNMT (HGNC:):

PNMT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14066604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNMT	NM_002686.4 linkuse as main transcript	c.134G>C	p.Gly45Ala	missense_variant	1/3	ENST00000269582.3	NP_002677.1	P11086
PNMT	NR_073461.2 linkuse as main transcript	n.52+539G>C		intron_variant
PNMT	XM_011524909.3 linkuse as main transcript	c.-505G>C		upstream_gene_variant			XP_011523211.1	A8MT87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PNMT	ENST00000269582.3 linkuse as main transcript	c.134G>C	p.Gly45Ala	missense_variant	1/3	1	NM_002686.4	ENSP00000269582.2	P11086
PNMT	ENST00000581428.1 linkuse as main transcript	c.134G>C	p.Gly45Ala	missense_variant	1/2	2		ENSP00000464234.1	J3QRI3
PNMT	ENST00000394246.1 linkuse as main transcript	c.-93+539G>C		intron_variant		2		ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229984

Hom.:

AF XY:

0.00000786

AC XY:

AN XY:

127238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000970

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1453694

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723286

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.134G>C (p.G45A) alteration is located in exon 1 (coding exon 1) of the PNMT gene. This alteration results from a G to C substitution at nucleotide position 134, causing the glycine (G) at amino acid position 45 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.16

Sift

Benign

0.43

T;.

Sift4G

Benign

0.30

T;T

Polyphen

0.15

B;.

Vest4

0.070

MutPred

0.55

Gain of glycosylation at P43 (P = 0.0912);Gain of glycosylation at P43 (P = 0.0912);

MVP

0.30

MPC

0.31

ClinPred

0.37

GERP RS

4.5

Varity_R

0.64

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over