17-39668528-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002686.4(PNMT):​c.53C>T​(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,542,696 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030217886).

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>T	p.Pro18Leu	missense	Exon 1 of 3	NP_002677.1	P11086
	PNMT	NR_073461.2		n.52+458C>T		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>T	p.Pro18Leu	missense	Exon 1 of 3	ENSP00000269582.2	P11086
	PNMT	ENST00000581428.1	TSL:2	c.53C>T	p.Pro18Leu	missense	Exon 1 of 2	ENSP00000464234.1	J3QRI3
	PNMT	ENST00000394246.1	TSL:2	c.-93+458C>T		intron	N/A	ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000213 AC: 3 AN: 140634 AF XY: 0.0000129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 24 AN: 1390496 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 686884

African (AFR) AF: 0.00 AC: 0 AN: 31678

American (AMR) AF: 0.0000271 AC: 1 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: 0.0000203 AC: 22 AN: 1082454

Other (OTH) AF: 0.0000173 AC: 1 AN: 57914

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000463 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000184 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.29
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.13
Sift	Uncertain	0.029	D
Sift4G	Benign	0.35	T
Polyphen		0.16	B
Vest4		0.092
MVP		0.33
MPC		0.24
ClinPred		0.077	T
GERP RS		4.0
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.62
Mutation Taster		=89/11	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;