2-25161179-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP4_Strong BS1 BS2

The NM_000939.4(POMC):c.706C>G(p.Arg236Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00434 in 1,613,852 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (28 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 B:3 O:1
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017676592).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00284 (433/152332) while in subpopulation AMR AF= 0.00542 (83/15304). AF 95% confidence interval is 0.00448. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMC	NM_000939.4	c.706C>G	p.Arg236Gly	missense_variant	3/3	ENST00000395826.7
POMC	NM_001035256.3	c.706C>G	p.Arg236Gly	missense_variant	4/4
POMC	NM_001319204.2	c.706C>G	p.Arg236Gly	missense_variant	4/4
POMC	NM_001319205.2	c.706C>G	p.Arg236Gly	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7	c.706C>G	p.Arg236Gly	missense_variant	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 433 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00269 AC: 675 AN: 250890 Hom.: 3 AF XY: 0.00259 AC XY: 352 AN XY: 135696

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00449 AC: 6569 AN: 1461520 Hom.: 28 Cov.: 32 AF XY: 0.00436 AC XY: 3173 AN XY: 727076

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74494

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00398 Hom.: 0

Bravo AF: 0.00357

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	The R236G variant in the POMC gene has been reported previously in the heterozygous state in multiple individuals with obesity (Miraglia del Giudice et al., 2001; Challis et al., 2002; Buono et al., 2005; Lee et al., 2006; Creemers et al., 2008; Dubern et al., 2008; Shabana et al., 2016; Nordang et al., 2017). While it has also been reported in control populations, the frequency appears to be higher in individuals with obesity, and R236G is felt to confer an increased risk for obesity (Shabana et al., 2016). The R236G variant is observed in 234/66,206 (0.35%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R236G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution disrupts the dibasic cleavage site at a position that is conserved across species (Challis et al., 2002). Functional studies demonstrate that R236G is associated with expression of an abnormal fusion protein that interferes with MC4R signaling (Challis et al., 2002). We interpret R236G as a risk allele. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Obesity due to pro-opiomelanocortin deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2022	_x000D_ Criteria applied: PS3_SUP, PS4_SUP, PP1, PP3 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 26, 2023

- -

POMC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Obesity, early-onset, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;D;D;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;.;.;.;T
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.6	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.4	D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.98
MVP		0.96
MPC		1.1
ClinPred		0.048	T
GERP RS		4.2
Varity_R		0.82
gMVP		0.68

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

Other links and lift over

dbSNP: rs28932472; hg19: chr2-25384048; COSMIC: COSV99063086; COSMIC: COSV99063086;