2-25162769-A-G

Variant names:

• chr2-25162769-A-G
• rs7565427
• NM_000939.4:c.133-1017T>C

Variant summary

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

The ENST00000395826.7(POMC):​c.133-1017T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.888 in 152,246 control chromosomes in the GnomAD database, including 60,117 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 0.89 (60117 hom., cov: 32)
• Consequence: POMC ENST00000395826.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.935
• Publications: 13 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395826.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.133-1017T>C		intron	N/A	NP_000930.1
	POMC	NM_001035256.3		c.133-1017T>C		intron	N/A	NP_001030333.1
	POMC	NM_001319204.2		c.133-1017T>C		intron	N/A	NP_001306133.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.133-1017T>C		intron	N/A	ENSP00000379170.2
	POMC	ENST00000405623.5	TSL:1	c.133-1017T>C		intron	N/A	ENSP00000384092.1
	POMC	ENST00000264708.7	TSL:2	c.133-1017T>C		intron	N/A	ENSP00000264708.3

Frequencies

GnomAD3 genomes AF: 0.888 AC: 135087 AN: 152128 Hom.: 60059 Cov.: 32

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.879

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.892

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

GnomAD4 genome AF: 0.888 AC: 135203 AN: 152246 Hom.: 60117 Cov.: 32 AF XY: 0.892 AC XY: 66390 AN XY: 74430

African (AFR) AF: 0.896 AC: 37220 AN: 41544

American (AMR) AF: 0.915 AC: 13998 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2849 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5176 AN: 5180

South Asian (SAS) AF: 0.952 AC: 4584 AN: 4814

European-Finnish (FIN) AF: 0.879 AC: 9320 AN: 10600

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.868 AC: 59030 AN: 68012

Other (OTH) AF: 0.893 AC: 1887 AN: 2114

Alfa AF: 0.872 Hom.: 64775

Bravo AF: 0.891

Asia WGS AF: 0.970 AC: 3372 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	9.7
DANN	Benign	0.39
PhyloP100		0.94
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: rs7565427; hg19: chr2-25385638;