chr17-39669781-G-C

Position:

• chr17-39669781-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002686.4(PNMT):​c.355G>C​(p.Gly119Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 4.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNMT	NM_002686.4	c.355G>C	p.Gly119Arg	missense_variant	2/3	ENST00000269582.3	NP_002677.1
PNMT	XM_011524909.3	c.61G>C	p.Gly21Arg	missense_variant	2/3		XP_011523211.1
PNMT	NR_073461.2	n.205G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.355G>C	p.Gly119Arg	missense_variant	2/3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000394246.1	c.61G>C	p.Gly21Arg	missense_variant	2/3	2		ENSP00000377791.1
PNMT	ENST00000581428.1	c.355G>C	p.Gly119Arg	missense_variant	2/2	2		ENSP00000464234.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 22, 2023

The c.355G>C (p.G119R) alteration is located in exon 2 (coding exon 2) of the PNMT gene. This alteration results from a G to C substitution at nucleotide position 355, causing the glycine (G) at amino acid position 119 to be replaced by an arginine (R). 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	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.
Eigen	Benign	0.083
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.1	D;D;.
REVEL	Benign	0.15
Sift	Uncertain	0.014	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95	.;P;.
Vest4		0.47
MutPred		0.84		.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);
MVP		0.38
MPC		0.72
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.74
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-37826034;