2-25161052-GA-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000939.4(POMC):c.*28del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,858 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: POMC NM_000939.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.23

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 Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.001 (153/152342) while in subpopulation NFE AF= 0.00201 (137/68030). AF 95% confidence interval is 0.00174. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMC	NM_000939.4	c.*28del		3_prime_UTR_variant	3/3	ENST00000395826.7
POMC	NM_001035256.3	c.*28del		3_prime_UTR_variant	4/4
POMC	NM_001319204.2	c.*28del		3_prime_UTR_variant	4/4
POMC	NM_001319205.2	c.*28del		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7	c.*28del		3_prime_UTR_variant	3/3	2	NM_000939.4	P1
POMC	ENST00000405623.5	c.*28del		3_prime_UTR_variant	3/3	1		P1
POMC	ENST00000264708.7	c.*28del		3_prime_UTR_variant	4/4	2		P1
POMC	ENST00000380794.5	c.*28del		3_prime_UTR_variant	4/4	2		P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000915 AC: 228 AN: 249178 Hom.: 0 AF XY: 0.000991 AC XY: 134 AN XY: 135280

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.00157 AC: 2298 AN: 1461516 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 1081 AN XY: 727080

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74500

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.00102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Monogenic Non-Syndromic Obesity Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to pro-opiomelanocortin deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs756770132; hg19: chr2-25383921;