rs201408477
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_000939.4(POMC):āc.430T>Cā(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 (ā ā ).
Frequency
Genomes: š 0.00018 ( 0 hom., cov: 33)
Exomes š: 0.00018 ( 1 hom. )
Consequence
POMC
NM_000939.4 missense
NM_000939.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.08
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]
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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 | UniProt |
---|---|---|---|---|---|---|---|
POMC | NM_000939.4 | c.430T>C | p.Phe144Leu | missense_variant | 3/3 | ENST00000395826.7 | |
POMC | NM_001035256.3 | c.430T>C | p.Phe144Leu | missense_variant | 4/4 | ||
POMC | NM_001319204.2 | c.430T>C | p.Phe144Leu | missense_variant | 4/4 | ||
POMC | NM_001319205.2 | c.430T>C | p.Phe144Leu | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMC | ENST00000395826.7 | c.430T>C | p.Phe144Leu | missense_variant | 3/3 | 2 | NM_000939.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152168Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000182 AC: 43AN: 236636Hom.: 0 AF XY: 0.000177 AC XY: 23AN XY: 130230
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GnomAD4 exome AF: 0.000185 AC: 269AN: 1457868Hom.: 1 Cov.: 32 AF XY: 0.000177 AC XY: 128AN XY: 725182
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GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74486
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;.
Polyphen
D;D;D;D;.
Vest4
MutPred
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
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at