chr2-25161018-G-A

Variant names:

• chr2-25161018-G-A
• rs1042571
• NM_000939.4:c.*63C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 30 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.*63C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.*63C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.*63C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.*63C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.*63C>T		3_prime_UTR_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2

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

African (AFR) AF: 0.121 AC: 4039 AN: 33292

American (AMR) AF: 0.115 AC: 5091 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5825 AN: 25934

East Asian (EAS) AF: 0.0101 AC: 399 AN: 39622

South Asian (SAS) AF: 0.0917 AC: 7888 AN: 86052

European-Finnish (FIN) AF: 0.101 AC: 5188 AN: 51390

Middle Eastern (MID) AF: 0.190 AC: 1081 AN: 5692

European-Non Finnish (NFE) AF: 0.192 AC: 212886 AN: 1109430

Other (OTH) AF: 0.167 AC: 10040 AN: 60064

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

African (AFR) AF: 0.125 AC: 5207 AN: 41580

American (AMR) AF: 0.164 AC: 2502 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 790 AN: 3472

East Asian (EAS) AF: 0.0175 AC: 91 AN: 5194

South Asian (SAS) AF: 0.0855 AC: 413 AN: 4828

European-Finnish (FIN) AF: 0.0935 AC: 993 AN: 10620

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12813 AN: 68002

Other (OTH) AF: 0.176 AC: 373 AN: 2116

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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14513068, 23028917, 23315997) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Obesity Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042571; hg19: chr2-25383887;