rs201408477

Positions:

chr2-25161455-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting

The NM_000939.4(POMC):c.430T>C(p.Phe144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,610,154 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 (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

POMC
NM_000939.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.08

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000184 (28/152286) while in subpopulation NFE AF= 0.000323 (22/68016). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 12 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.430T>C	p.Phe144Leu	missense_variant	3/3	ENST00000395826.7
POMC	NM_001035256.3 linkuse as main transcript	c.430T>C	p.Phe144Leu	missense_variant	4/4
POMC	NM_001319204.2 linkuse as main transcript	c.430T>C	p.Phe144Leu	missense_variant	4/4
POMC	NM_001319205.2 linkuse as main transcript	c.430T>C	p.Phe144Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.430T>C	p.Phe144Leu	missense_variant	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000182

AC:

AN:

236636

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

130230

show subpopulations

Gnomad AFR exome

AF:

0.0000741

Gnomad AMR exome

AF:

0.0000884

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000310

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000185

AC:

269

AN:

1457868

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

128

AN XY:

725182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000206

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000184

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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	Mar 23, 2023	This variant is also known as Phe118Leu. This missense change has been observed in individual(s) with early onset obesity (PMID: 18091355). This variant is present in population databases (rs201408477, gnomAD 0.03%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 144 of the POMC protein (p.Phe144Leu). ClinVar contains an entry for this variant (Variation ID: 596626). 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. Experimental studies have shown that this missense change affects POMC function (PMID: 18091355). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POMC protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2018	- -

POMC-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The POMC c.430T>C variant is predicted to result in the amino acid substitution p.Phe144Leu. This variant was reported to segregate with obesity in a two-generation pedigree, and in vitro analysis suggested that MC4R signaling was nearly abolished due to reduced alpha-MSH binding (Dubern et al. 2008. PubMed ID: 18091355). Another in vitro functional study also showed strong evidence of loss of function (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). However, in a second study, this variant was found in three non-obese sisters, suggesting that it may be a benign polymorphism (Philippe et al. 2015. PubMed ID: 24890885). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;D;D;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;.;.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.8

M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.96

MutPred

0.86

Gain of catalytic residue at F144 (P = 0.0055);Gain of catalytic residue at F144 (P = 0.0055);Gain of catalytic residue at F144 (P = 0.0055);Gain of catalytic residue at F144 (P = 0.0055);Gain of catalytic residue at F144 (P = 0.0055);

MVP

0.98

MPC

1.1

ClinPred

0.84

GERP RS

4.0

Varity_R

0.91

gMVP

0.74

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