2-25161269-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongPM2BS1_Supporting

The NM_000939.4(POMC):c.616G>T(p.Glu206Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,611,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E206E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

POMC
NM_000939.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.55

Variant links:

Genes affected

POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]

POMC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.234 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000381 (58/152142) while in subpopulation NFE AF= 0.000647 (44/67974). AF 95% confidence interval is 0.000495. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POMC	NM_000939.4 linkuse as main transcript	c.616G>T	p.Glu206Ter	stop_gained	3/3	ENST00000395826.7
POMC	NM_001035256.3 linkuse as main transcript	c.616G>T	p.Glu206Ter	stop_gained	4/4
POMC	NM_001319204.2 linkuse as main transcript	c.616G>T	p.Glu206Ter	stop_gained	4/4
POMC	NM_001319205.2 linkuse as main transcript	c.616G>T	p.Glu206Ter	stop_gained	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.616G>T	p.Glu206Ter	stop_gained	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000412

AC:

101

AN:

245020

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

133230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00168

Gnomad NFE exome

AF:

0.000570

Gnomad OTH exome

AF:

0.000501

GnomAD4 exome

AF:

0.000345

AC:

504

AN:

1459684

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

252

AN XY:

726000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00145

Gnomad4 NFE exome

AF:

0.000369

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000381

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000488

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000238

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Glu206*) in the POMC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the POMC protein. This variant is present in population databases (rs202127120, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with obesity, in cis with a nearby in-frame insertion (PMID: 9768693, 29970488, 35574020). This variant is also known as Glu-180-Stop. ClinVar contains an entry for this variant (Variation ID: 381722). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2017	The E206X variant in the POMC gene has been reported previously according to alternate nomeclature, in cis with an in-frame duplication variant (c.599_604dupGGGCCC) and in trans with a missense variant (E214G), in a German adolescent female with obesity (Hinney et al., 1998). This variant causes the loss of the last 62 amino acid residues and is predicted to cause loss of normal protein function through protein truncation. The E206X variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, we interpret E206X as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.47

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.83

GERP RS

4.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over