rs760778798

Variant names:

• chr17-39669647-C-G
• rs760778798
• NM_002686.4:c.221C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-39669647-C-G
• chr17-39669647-C-T

Variant summary

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

The NM_002686.4(PNMT):​c.221C>G​(p.Thr74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNMT NM_002686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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

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=0.2525741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMT	NM_002686.4	c.221C>G	p.Thr74Ser	missense_variant	Exon 2 of 3	ENST00000269582.3	NP_002677.1
PNMT	XM_011524909.3	c.-74C>G		5_prime_UTR_variant	Exon 2 of 3		XP_011523211.1
PNMT	NR_073461.2	n.71C>G		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNMT	ENST00000269582.3	c.221C>G	p.Thr74Ser	missense_variant	Exon 2 of 3	1	NM_002686.4	ENSP00000269582.2
PNMT	ENST00000581428.1	c.221C>G	p.Thr74Ser	missense_variant	Exon 2 of 2	2		ENSP00000464234.1
PNMT	ENST00000394246	c.-74C>G		5_prime_UTR_variant	Exon 2 of 3	2		ENSP00000377791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.070
Sift	Benign	0.15	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.70		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);
MVP		0.22
MPC		0.22
ClinPred		0.079	T
GERP RS		2.5
Varity_R		0.31
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs760778798; hg19: chr17-37825900;