2-25166355-A-G

Variant names:

• chr2-25166355-A-G
• rs934778
• NM_000939.4:c.-20-1563T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000939.4(POMC):​c.-20-1563T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,252 control chromosomes in the GnomAD database, including 4,608 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (4608 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 39 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• inherited obesity

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.-20-1563T>C		intron	N/A	NP_000930.1	P01189
	POMC	NM_001035256.3		c.-70-670T>C		intron	N/A	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.-100-670T>C		intron	N/A	NP_001306133.1	P01189

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.-20-1563T>C		intron	N/A	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.-50-1533T>C		intron	N/A	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.-100-670T>C		intron	N/A	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33966 AN: 152134 Hom.: 4608 Cov.: 32

Gnomad AFR AF: 0.0862

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.266

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.223 AC: 33964 AN: 152252 Hom.: 4608 Cov.: 32 AF XY: 0.218 AC XY: 16228 AN XY: 74454

African (AFR) AF: 0.0862 AC: 3581 AN: 41554

American (AMR) AF: 0.261 AC: 3985 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1143 AN: 3472

East Asian (EAS) AF: 0.121 AC: 629 AN: 5184

South Asian (SAS) AF: 0.237 AC: 1146 AN: 4828

European-Finnish (FIN) AF: 0.164 AC: 1739 AN: 10604

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20844 AN: 68004

Other (OTH) AF: 0.263 AC: 557 AN: 2116

Alfa AF: 0.277 Hom.: 22007

Bravo AF: 0.224

Asia WGS AF: 0.167 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.51
PhyloP100		-0.20
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: rs934778; hg19: chr2-25389224;