chr17-39668598-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_002686.4(PNMT):​c.123G>T​(p.Ala41Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A41A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PNMT NM_002686.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP7: Synonymous conserved (PhyloP=0.194 with no splicing effect.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450914 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721794

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 85430

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 46036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

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

Other (OTH) AF: 0.00 AC: 0 AN: 60140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.19
PromoterAI		-0.090	Neutral

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: rs62639962; hg19: chr17-37824851;