rs2071345

Variant summary

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

The NM_000939.4(POMC):c.585C>T(p.Ala195=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,609,920 control chromosomes in the GnomAD database, including 2,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 305 hom., cov: 33)

Exomes 𝑓: 0.019 ( 2315 hom. )

Consequence

POMC
NM_000939.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0880

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=-0.84).

BP6

Variant 2-25161300-G-A is Benign according to our data. Variant chr2-25161300-G-A is described in ClinVar as [Benign]. Clinvar id is 335354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.088 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
POMC	NM_000939.4 linkuse as main transcript	c.585C>T	p.Ala195=	synonymous_variant	3/3	ENST00000395826.7
POMC	NM_001035256.3 linkuse as main transcript	c.585C>T	p.Ala195=	synonymous_variant	4/4
POMC	NM_001319204.2 linkuse as main transcript	c.585C>T	p.Ala195=	synonymous_variant	4/4
POMC	NM_001319205.2 linkuse as main transcript	c.585C>T	p.Ala195=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.585C>T	p.Ala195=	synonymous_variant	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

3419

AN:

152150

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.0970

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.0292

GnomAD3 exomes

AF:

0.0472

AC:

11174

AN:

236732

Hom.:

1098

AF XY:

0.0459

AC XY:

5937

AN XY:

129296

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.00782

Gnomad EAS exome

AF:

0.325

Gnomad SAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.0444

Gnomad NFE exome

AF:

0.00369

Gnomad OTH exome

AF:

0.0239

GnomAD4 exome

AF:

0.0185

AC:

26967

AN:

1457652

Hom.:

2315

Cov.:

AF XY:

0.0200

AC XY:

14475

AN XY:

724902

show subpopulations

Gnomad4 AFR exome

AF:

0.00183

Gnomad4 AMR exome

AF:

0.0417

Gnomad4 ASJ exome

AF:

0.00771

Gnomad4 EAS exome

AF:

0.299

Gnomad4 SAS exome

AF:

0.0799

Gnomad4 FIN exome

AF:

0.0435

Gnomad4 NFE exome

AF:

0.00207

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0224

AC:

3413

AN:

152268

Hom.:

305

Cov.:

AF XY:

0.0273

AC XY:

2033

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00265

Gnomad4 AMR

AF:

0.0274

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.309

Gnomad4 SAS

AF:

0.0977

Gnomad4 FIN

AF:

0.0434

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.161

AC:

557

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Obesity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

5.2

Dann

Benign

0.58

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