2-25164312-T-G

Variant names:

• chr2-25164312-T-G
• rs12473543
• NM_000939.4:c.132+329A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000939.4(POMC):​c.132+329A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 152,002 control chromosomes in the GnomAD database, including 5,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (5563 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-25164312-T-G is Benign according to our data. Variant chr2-25164312-T-G is described in ClinVar as Benign. ClinVar VariationId is 1258300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.132+329A>C		intron_variant	Intron 2 of 2	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.132+329A>C		intron_variant	Intron 3 of 3		NP_001030333.1
POMC	NM_001319204.2	c.132+329A>C		intron_variant	Intron 3 of 3		NP_001306133.1
POMC	NM_001319205.2	c.132+329A>C		intron_variant	Intron 2 of 2		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.132+329A>C		intron_variant	Intron 2 of 2	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37682 AN: 151884 Hom.: 5546 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.248 AC: 37714 AN: 152002 Hom.: 5563 Cov.: 32 AF XY: 0.265 AC XY: 19696 AN XY: 74320

African (AFR) AF: 0.182 AC: 7528 AN: 41466

American (AMR) AF: 0.383 AC: 5841 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3104 AN: 5168

South Asian (SAS) AF: 0.384 AC: 1845 AN: 4806

European-Finnish (FIN) AF: 0.378 AC: 3986 AN: 10546

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14015 AN: 67954

Other (OTH) AF: 0.234 AC: 494 AN: 2114

Alfa AF: 0.228 Hom.: 493

Bravo AF: 0.248

Asia WGS AF: 0.448 AC: 1558 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.3
DANN	Benign	0.58
PhyloP100		1.1
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: rs12473543; hg19: chr2-25387181;