chr17-39668598-G-A

Variant names:

• chr17-39668598-G-A
• rs62639962
• NM_002686.4:c.123G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002686.4(PNMT):​c.123G>A​(p.Ala41Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,603,234 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (4 hom.)
• Consequence: PNMT NM_002686.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.194

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 17-39668598-G-A is Benign according to our data. Variant chr17-39668598-G-A is described in ClinVar as [Benign]. Clinvar id is 720757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.194 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00598 (911/152324) while in subpopulation AFR AF = 0.0207 (861/41562). AF 95% confidence interval is 0.0196. There are 6 homozygotes in GnomAd4. There are 454 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NM_002686.4	c.123G>A	p.Ala41Ala	synonymous_variant	Exon 1 of 3	ENST00000269582.3	NP_002677.1
PNMT	NR_073461.2	n.52+528G>A		intron_variant	Intron 1 of 2
PNMT	XM_011524909.3	c.-516G>A		upstream_gene_variant			XP_011523211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.123G>A	p.Ala41Ala	synonymous_variant	Exon 1 of 3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000581428.1	c.123G>A	p.Ala41Ala	synonymous_variant	Exon 1 of 2	2		ENSP00000464234.1
PNMT	ENST00000394246.1	c.-93+528G>A		intron_variant	Intron 1 of 2	2		ENSP00000377791.1

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 912 AN: 152208 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00149 AC: 335 AN: 225372 AF XY: 0.00110

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.000707

GnomAD4 exome AF: 0.000567 AC: 822 AN: 1450910 Hom.: 4 Cov.: 32 AF XY: 0.000447 AC XY: 323 AN XY: 721790

African (AFR) AF: 0.0210 AC: 700 AN: 33318

American (AMR) AF: 0.00117 AC: 52 AN: 44336

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

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

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85430

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 46034

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5736

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1110432

Other (OTH) AF: 0.000898 AC: 54 AN: 60140

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152324 Hom.: 6 Cov.: 33 AF XY: 0.00609 AC XY: 454 AN XY: 74498

African (AFR) AF: 0.0207 AC: 861 AN: 41562

American (AMR) AF: 0.00274 AC: 42 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00605 Hom.: 6

Bravo AF: 0.00714

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.19
PromoterAI		-0.16	Neutral
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs62639962; hg19: chr17-37824851;