dbSNP rs747980015: PNMT:p.Arg37Gly (chr17-39668584-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_002686.4(PNMT):c.109C>G(p.Arg37Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,599,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PNMT
NM_002686.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.18

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 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=0.24735487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NM_002686.4 link	c.109C>G	p.Arg37Gly	missense_variant	Exon 1 of 3	ENST00000269582.3	NP_002677.1	P11086
PNMT	NR_073461.2 link	n.52+514C>G		intron_variant	Intron 1 of 2
PNMT	XM_011524909.3 link	c.-530C>G		upstream_gene_variant			XP_011523211.1	A8MT87

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNMT	ENST00000269582.3 link	c.109C>G	p.Arg37Gly	missense_variant	Exon 1 of 3	1	NM_002686.4	ENSP00000269582.2	P11086
PNMT	ENST00000581428.1 link	c.109C>G	p.Arg37Gly	missense_variant	Exon 1 of 2	2		ENSP00000464234.1	J3QRI3
PNMT	ENST00000394246.1 link	c.-93+514C>G		intron_variant	Intron 1 of 2	2		ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447484

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720034

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

T;.

Eigen

Benign

-0.033

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.074

Sift

Benign

0.22

T;.

Sift4G

Benign

0.37

T;T

Polyphen

0.66

P;.

Vest4

0.17

MutPred

0.49

Loss of stability (P = 0.0192);Loss of stability (P = 0.0192);

MVP

0.22

MPC

0.47

ClinPred

0.69

GERP RS

2.4

Varity_R

0.59

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over