17-39668597-C-T

Variant names:

• chr17-39668597-C-T
• rs760242109
• NM_002686.4:c.122C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002686.4(PNMT):​c.122C>T​(p.Ala41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,603,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A41A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.777
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.079387486).

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.122C>T	p.Ala41Val	missense	Exon 1 of 3	NP_002677.1	P11086
	PNMT	NR_073461.2		n.52+527C>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.122C>T	p.Ala41Val	missense	Exon 1 of 3	ENSP00000269582.2	P11086
	PNMT	ENST00000581428.1	TSL:2	c.122C>T	p.Ala41Val	missense	Exon 1 of 2	ENSP00000464234.1	J3QRI3
	PNMT	ENST00000394246.1	TSL:2	c.-93+527C>T		intron	N/A	ENSP00000377791.1	A8MT87

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000267 AC: 6 AN: 225084 AF XY: 0.0000321

Gnomad AFR exome AF: 0.000151

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1450730 Hom.: 0 Cov.: 31 AF XY: 0.0000236 AC XY: 17 AN XY: 721752

African (AFR) AF: 0.000150 AC: 5 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.000223 AC: 19 AN: 85374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110432

Other (OTH) AF: 0.0000499 AC: 3 AN: 60130

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74510

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000837 AC: 1

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	0.095
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.78
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.061
Sift	Benign	0.40	T
Sift4G	Benign	0.39	T
Polyphen		0.27	B
Vest4		0.067
MVP		0.22
MPC		0.24
ClinPred		0.070	T
GERP RS		3.5
PromoterAI		-0.13	Neutral
Varity_R		0.21
gMVP		0.48
Mutation Taster		=96/4	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: rs760242109; hg19: chr17-37824850;