chr17-39669637-T-G

Position:

• chr17-39669637-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002686.4(PNMT):​c.211T>G​(p.Ser71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0450

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]

PNMT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14958459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNMT	NM_002686.4	c.211T>G	p.Ser71Ala	missense_variant	2/3	ENST00000269582.3	NP_002677.1
PNMT	XM_011524909.3	c.-84T>G		5_prime_UTR_variant	2/3		XP_011523211.1
PNMT	NR_073461.2	n.61T>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.211T>G	p.Ser71Ala	missense_variant	2/3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000581428.1	c.211T>G	p.Ser71Ala	missense_variant	2/2	2		ENSP00000464234.1
PNMT	ENST00000394246.1	c.-84T>G		5_prime_UTR_variant	2/3	2		ENSP00000377791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.211T>G (p.S71A) alteration is located in exon 2 (coding exon 2) of the PNMT gene. This alteration results from a T to G substitution at nucleotide position 211, causing the serine (S) at amino acid position 71 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.037
Sift	Benign	0.44	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.035	B;.
Vest4		0.11
MutPred		0.41		Loss of glycosylation at S71 (P = 0.0259);Loss of glycosylation at S71 (P = 0.0259);
MVP		0.20
MPC		0.20
ClinPred		0.094	T
GERP RS		0.85
Varity_R		0.18
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1597807869; hg19: chr17-37825890;