rs5638

Variant names:

• chr17-39669996-A-G
• rs5638
• NM_002686.4:c.456A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002686.4(PNMT):​c.456A>G​(p.Lys152Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,603,634 control chromosomes in the GnomAD database, including 1,159 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.057 (473 hom., cov: 32)
  • Exomes 𝑓: 0.020 (686 hom.)
• Consequence: PNMT NM_002686.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=2.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NM_002686.4	c.456A>G	p.Lys152Lys	synonymous_variant	Exon 3 of 3	ENST00000269582.3	NP_002677.1
PNMT	XM_011524909.3	c.162A>G	p.Lys54Lys	synonymous_variant	Exon 3 of 3		XP_011523211.1
PNMT	NR_073461.2	n.306A>G		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.456A>G	p.Lys152Lys	synonymous_variant	Exon 3 of 3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000394246.1	c.162A>G	p.Lys54Lys	synonymous_variant	Exon 3 of 3	2		ENSP00000377791.1
PNMT	ENST00000581428.1	c.*156A>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000464234.1

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8576 AN: 151926 Hom.: 472 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0378

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0283 AC: 6865 AN: 242458 AF XY: 0.0264

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0243

GnomAD4 exome AF: 0.0202 AC: 29307 AN: 1451590 Hom.: 686 Cov.: 32 AF XY: 0.0206 AC XY: 14881 AN XY: 722300

African (AFR) AF: 0.139 AC: 4665 AN: 33446

American (AMR) AF: 0.0161 AC: 720 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 495 AN: 26072

East Asian (EAS) AF: 0.000555 AC: 22 AN: 39646

South Asian (SAS) AF: 0.0341 AC: 2939 AN: 86180

European-Finnish (FIN) AF: 0.0288 AC: 1286 AN: 44644

Middle Eastern (MID) AF: 0.0405 AC: 233 AN: 5758

European-Non Finnish (NFE) AF: 0.0155 AC: 17240 AN: 1110914

Other (OTH) AF: 0.0283 AC: 1707 AN: 60270

GnomAD4 genome AF: 0.0566 AC: 8605 AN: 152044 Hom.: 473 Cov.: 32 AF XY: 0.0564 AC XY: 4192 AN XY: 74318

African (AFR) AF: 0.146 AC: 6050 AN: 41448

American (AMR) AF: 0.0321 AC: 490 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5162

South Asian (SAS) AF: 0.0374 AC: 180 AN: 4812

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1410 AN: 67948

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

Alfa AF: 0.0329 Hom.: 485

Bravo AF: 0.0585

Asia WGS AF: 0.0330 AC: 117 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.9
DANN	Benign	0.69
PhyloP100		2.0
Mutation Taster		=99/1	polymorphism (auto)

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: rs5638; hg19: chr17-37826249;