rs3769671

Variant names:

• chr2-25167284-A-C
• rs3769671
• NM_000939.4:c.-21+1214T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-25167284-A-C
• chr2-25167284-A-T

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+1214T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 151,726 control chromosomes in the GnomAD database, including 147 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 0.039 (147 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652
• Publications: 9 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.-21+1214T>G		intron_variant	Intron 1 of 2	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.-71+1214T>G		intron_variant	Intron 1 of 3		NP_001030333.1
POMC	NM_001319204.2	c.-101+1214T>G		intron_variant	Intron 1 of 3		NP_001306133.1
POMC	NM_001319205.2	c.-51+1214T>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+1214T>G		intron_variant	Intron 1 of 2	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5964 AN: 151608 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0456

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0307

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

GnomAD4 genome AF: 0.0394 AC: 5976 AN: 151726 Hom.: 147 Cov.: 32 AF XY: 0.0410 AC XY: 3038 AN XY: 74136

African (AFR) AF: 0.0436 AC: 1805 AN: 41424

American (AMR) AF: 0.0456 AC: 686 AN: 15042

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.0429 AC: 222 AN: 5176

South Asian (SAS) AF: 0.110 AC: 516 AN: 4706

European-Finnish (FIN) AF: 0.0413 AC: 438 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2201 AN: 68006

Other (OTH) AF: 0.0304 AC: 64 AN: 2104

Alfa AF: 0.0305 Hom.: 10

Bravo AF: 0.0394

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.13
DANN	Benign	0.47
PhyloP100		-0.65
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: rs3769671; hg19: chr2-25390153;