rs1009388

Variant names:

• chr2-25168232-G-C
• rs1009388
• NM_000939.4:c.-21+266C>G

Variant summary

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

The NM_000939.4(POMC):​c.-21+266C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 151,960 control chromosomes in the GnomAD database, including 3,483 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 0.19 (3483 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.-21+266C>G		intron_variant	Intron 1 of 2	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.-71+266C>G		intron_variant	Intron 1 of 3		NP_001030333.1
POMC	NM_001319204.2	c.-101+266C>G		intron_variant	Intron 1 of 3		NP_001306133.1
POMC	NM_001319205.2	c.-51+266C>G		intron_variant	Intron 1 of 2		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.-21+266C>G		intron_variant	Intron 1 of 2	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28180 AN: 151862 Hom.: 3486 Cov.: 32

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.185 AC: 28170 AN: 151960 Hom.: 3483 Cov.: 32 AF XY: 0.178 AC XY: 13234 AN XY: 74256

African (AFR) AF: 0.0509 AC: 2113 AN: 41488

American (AMR) AF: 0.215 AC: 3282 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3470

East Asian (EAS) AF: 0.0656 AC: 338 AN: 5156

South Asian (SAS) AF: 0.120 AC: 576 AN: 4804

European-Finnish (FIN) AF: 0.128 AC: 1342 AN: 10516

Middle Eastern (MID) AF: 0.297 AC: 86 AN: 290

European-Non Finnish (NFE) AF: 0.274 AC: 18633 AN: 67956

Other (OTH) AF: 0.233 AC: 492 AN: 2108

Alfa AF: 0.220 Hom.: 548

Bravo AF: 0.186

Asia WGS AF: 0.0930 AC: 325 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.36
PhyloP100		-0.073
PromoterAI		-0.0092	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1009388; hg19: chr2-25391101;