rs28930368

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000939.4(POMC):c.282C>T(p.Ser94Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,556,648 control chromosomes in the GnomAD database, including 2,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 315 hom., cov: 33)

Exomes 𝑓: 0.018 ( 2163 hom. )

Consequence

POMC
NM_000939.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.10

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-25161603-G-A is Benign according to our data. Variant chr2-25161603-G-A is described in ClinVar as [Benign]. Clinvar id is 335356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25161603-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.1 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4 linkuse as main transcript	c.282C>T	p.Ser94Ser	synonymous_variant	3/3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 linkuse as main transcript	c.282C>T	p.Ser94Ser	synonymous_variant	4/4		NP_001030333.1	P01189
POMC	NM_001319204.2 linkuse as main transcript	c.282C>T	p.Ser94Ser	synonymous_variant	4/4		NP_001306133.1	P01189
POMC	NM_001319205.2 linkuse as main transcript	c.282C>T	p.Ser94Ser	synonymous_variant	3/3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.282C>T	p.Ser94Ser	synonymous_variant	3/3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3488

AN:

152064

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.0282

GnomAD3 exomes

AF:

0.0524

AC:

8031

AN:

153260

Hom.:

781

AF XY:

0.0535

AC XY:

4430

AN XY:

82766

show subpopulations

Gnomad AFR exome

AF:

0.00267

Gnomad AMR exome

AF:

0.0422

Gnomad ASJ exome

AF:

0.00838

Gnomad EAS exome

AF:

0.327

Gnomad SAS exome

AF:

0.0933

Gnomad FIN exome

AF:

0.0448

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0182

AC:

25513

AN:

1404470

Hom.:

2163

Cov.:

AF XY:

0.0201

AC XY:

13952

AN XY:

693614

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.0396

Gnomad4 ASJ exome

AF:

0.00774

Gnomad4 EAS exome

AF:

0.293

Gnomad4 SAS exome

AF:

0.0906

Gnomad4 FIN exome

AF:

0.0439

Gnomad4 NFE exome

AF:

0.00203

Gnomad4 OTH exome

AF:

0.0273

GnomAD4 genome

AF:

0.0229

AC:

3480

AN:

152178

Hom.:

315

Cov.:

AF XY:

0.0279

AC XY:

2076

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00275

Gnomad4 AMR

AF:

0.0276

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.308

Gnomad4 SAS

AF:

0.110

Gnomad4 FIN

AF:

0.0433

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.0275

Alfa

AF:

0.00791

Hom.:

Bravo

AF:

0.0229

Asia WGS

AF:

0.165

AC:

572

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Obesity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Obesity due to pro-opiomelanocortin deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.8

DANN

Benign

0.81

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