17-39670159-C-T

Position:

• chr17-39670159-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002686.4(PNMT):​c.619C>T​(p.Pro207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNMT	NM_002686.4	c.619C>T	p.Pro207Ser	missense_variant	3/3	ENST00000269582.3	NP_002677.1
PNMT	XM_011524909.3	c.325C>T	p.Pro109Ser	missense_variant	3/3		XP_011523211.1
PNMT	NR_073461.2	n.469C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.619C>T	p.Pro207Ser	missense_variant	3/3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000394246.1	c.325C>T	p.Pro109Ser	missense_variant	3/3	2		ENSP00000377791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.619C>T (p.P207S) alteration is located in exon 3 (coding exon 3) of the PNMT gene. This alteration results from a C to T substitution at nucleotide position 619, causing the proline (P) at amino acid position 207 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.079	T;D
Polyphen		0.0020	.;B
Vest4		0.20
MutPred		0.84		.;Gain of catalytic residue at P207 (P = 0.0267);
MVP		0.57
MPC		0.30
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.68
gMVP		0.60

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

Other links and lift over

dbSNP: rs1390523840; hg19: chr17-37826412;