17-39668537-C-G

Variant names:

• chr17-39668537-C-G
• rs1048359653
• NM_002686.4:c.62C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002686.4(PNMT):​c.62C>G​(p.Ala21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A21E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• Publications: 0 publications found

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]

ACMG classification

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=0.11191207).

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>G	p.Ala21Gly	missense	Exon 1 of 3	NP_002677.1	P11086
	PNMT	NR_073461.2		n.52+467C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNMT	ENST00000269582.3	TSL:1 MANE Select	c.62C>G	p.Ala21Gly	missense	Exon 1 of 3	ENSP00000269582.2	P11086
	PNMT	ENST00000581428.1	TSL:2	c.62C>G	p.Ala21Gly	missense	Exon 1 of 2	ENSP00000464234.1	J3QRI3
	PNMT	ENST00000394246.1	TSL:2	c.-93+467C>G		intron	N/A	ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394266 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688976

African (AFR) AF: 0.00 AC: 0 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 37206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36600

South Asian (SAS) AF: 0.00 AC: 0 AN: 79774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084260

Other (OTH) AF: 0.00 AC: 0 AN: 58060

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.096
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.066
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.34	T
Polyphen		0.068	B
Vest4		0.11
MutPred		0.56		Loss of helix (P = 0.079)
MVP		0.076
MPC		0.53
ClinPred		0.74	D
GERP RS		-4.9
PromoterAI		0.12	Neutral
Varity_R		0.30
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1048359653; hg19: chr17-37824790;