rs758623328

Variant names:

• chr17-39668528-C-G
• rs758623328
• NM_002686.4:c.53C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-39668528-C-G
• chr17-39668528-C-T

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.53C>G​(p.Pro18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,494 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. P18L) 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: 0.290
• 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=0.15476418).

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.53C>G	p.Pro18Arg	missense	Exon 1 of 3	NP_002677.1	P11086
	PNMT	NR_073461.2		n.52+458C>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.53C>G	p.Pro18Arg	missense	Exon 1 of 3	ENSP00000269582.2	P11086
	PNMT	ENST00000581428.1	TSL:2	c.53C>G	p.Pro18Arg	missense	Exon 1 of 2	ENSP00000464234.1	J3QRI3
	PNMT	ENST00000394246.1	TSL:2	c.-93+458C>G		intron	N/A	ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390494 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 686882

African (AFR) AF: 0.00 AC: 0 AN: 31676

American (AMR) AF: 0.00 AC: 0 AN: 36918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 36304

South Asian (SAS) AF: 0.00 AC: 0 AN: 79498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4658

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082454

Other (OTH) AF: 0.00 AC: 0 AN: 57914

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.9
DANN	Benign	0.90
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.29
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.11
Sift	Uncertain	0.023	D
Sift4G	Benign	0.10	T
Polyphen		0.17	B
Vest4		0.18
MutPred		0.42		Gain of MoRF binding (P = 0.004)
MVP		0.28
MPC		0.44
ClinPred		0.14	T
GERP RS		4.0
PromoterAI		-0.0023	Neutral
Varity_R		0.26
gMVP		0.66
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs758623328; hg19: chr17-37824781;