2-25161018-G-A

Position:

• chr2-25161018-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000939.4(POMC):​c.*63C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,607,892 control chromosomes in the GnomAD database, including 25,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2078 hom., cov: 33)
  • Exomes 𝑓: 0.17 (23535 hom.)
• Consequence: POMC NM_000939.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.880

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-25161018-G-A is Benign according to our data. Variant chr2-25161018-G-A is described in ClinVar as [Benign]. Clinvar id is 335352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4	c.*63C>T		3_prime_UTR_variant	3/3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.*63C>T		3_prime_UTR_variant	4/4		NP_001030333.1
POMC	NM_001319204.2	c.*63C>T		3_prime_UTR_variant	4/4		NP_001306133.1
POMC	NM_001319205.2	c.*63C>T		3_prime_UTR_variant	3/3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.*63C>T		3_prime_UTR_variant	3/3	2	NM_000939.4	ENSP00000379170	P1
POMC	ENST00000405623.5	c.*63C>T		3_prime_UTR_variant	3/3	1		ENSP00000384092	P1
POMC	ENST00000264708.7	c.*63C>T		3_prime_UTR_variant	4/4	2		ENSP00000264708	P1
POMC	ENST00000380794.5	c.*63C>T		3_prime_UTR_variant	4/4	2		ENSP00000370171	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23472 AN: 152192 Hom.: 2074 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0175

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.173 AC: 252437 AN: 1455582 Hom.: 23535 Cov.: 32 AF XY: 0.172 AC XY: 124253 AN XY: 723870

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.0917

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.154 AC: 23484 AN: 152310 Hom.: 2078 Cov.: 33 AF XY: 0.149 AC XY: 11119 AN XY: 74478

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.0855

Gnomad4 FIN AF: 0.0935

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.176

Alfa AF: 0.162 Hom.: 292

Bravo AF: 0.158

Asia WGS AF: 0.0560 AC: 198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	This variant is associated with the following publications: (PMID: 14513068, 23028917, 23315997) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Obesity Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.1
DANN	Benign	0.72

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: rs1042571; hg19: chr2-25383887;