rs934778

Positions:

• chr2-25166355-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4	c.-20-1563T>C		intron_variant		ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.-70-670T>C		intron_variant			NP_001030333.1
POMC	NM_001319204.2	c.-100-670T>C		intron_variant			NP_001306133.1
POMC	NM_001319205.2	c.-50-1533T>C		intron_variant			NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.-20-1563T>C		intron_variant		2	NM_000939.4	ENSP00000379170	P1

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

Gnomad4 AFR AF: 0.0862

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.263

Alfa AF: 0.292 Hom.: 10140

Bravo AF: 0.224

Asia WGS AF: 0.167 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.51

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: rs934778; hg19: chr2-25389224;