rs201408477

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

obesity due to pro-opiomelanocortin deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
inherited obesity
Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

POMC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 3 of 3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

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

GnomAD2 exomes

AF:

0.000182

AC:

AN:

236636

AF XY:

0.000177

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33432

American (AMR)

AF:

0.0000899

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000163

AC:

AN:

85762

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51370

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000206

AC:

229

AN:

1111186

Other (OTH)

AF:

0.000266

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41566

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Mar 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 20, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POMC-related disorder

Uncertain:1

May 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

9.1

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

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over