rs28930368

Variant names:

• chr2-25161603-G-A
• rs28930368
• NM_000939.4:c.282C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-25161603-G-A
• chr2-25161603-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000939.4(POMC):​c.282C>T​(p.Ser94Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,556,648 control chromosomes in the GnomAD database, including 2,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (315 hom., cov: 33)
  • Exomes 𝑓: 0.018 (2163 hom.)
• Consequence: POMC NM_000939.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.10
• Publications: 7 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• inherited obesity

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-25161603-G-A is Benign according to our data. Variant chr2-25161603-G-A is described in ClinVar as Benign. ClinVar VariationId is 335356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.282C>T	p.Ser94Ser	synonymous	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.282C>T	p.Ser94Ser	synonymous	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.282C>T	p.Ser94Ser	synonymous	Exon 4 of 4	NP_001306133.1	P01189

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.282C>T	p.Ser94Ser	synonymous	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.282C>T	p.Ser94Ser	synonymous	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.282C>T	p.Ser94Ser	synonymous	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3488 AN: 152064 Hom.: 315 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0524 AC: 8031 AN: 153260 AF XY: 0.0535

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.0422

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.327

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0182 AC: 25513 AN: 1404470 Hom.: 2163 Cov.: 33 AF XY: 0.0201 AC XY: 13952 AN XY: 693614

African (AFR) AF: 0.00179 AC: 57 AN: 31886

American (AMR) AF: 0.0396 AC: 1444 AN: 36492

Ashkenazi Jewish (ASJ) AF: 0.00774 AC: 195 AN: 25206

East Asian (EAS) AF: 0.293 AC: 10604 AN: 36176

South Asian (SAS) AF: 0.0906 AC: 7255 AN: 80054

European-Finnish (FIN) AF: 0.0439 AC: 2126 AN: 48410

Middle Eastern (MID) AF: 0.00790 AC: 45 AN: 5698

European-Non Finnish (NFE) AF: 0.00203 AC: 2197 AN: 1082344

Other (OTH) AF: 0.0273 AC: 1590 AN: 58204

GnomAD4 genome AF: 0.0229 AC: 3480 AN: 152178 Hom.: 315 Cov.: 33 AF XY: 0.0279 AC XY: 2076 AN XY: 74406

African (AFR) AF: 0.00275 AC: 114 AN: 41512

American (AMR) AF: 0.0276 AC: 422 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1591 AN: 5160

South Asian (SAS) AF: 0.110 AC: 529 AN: 4816

European-Finnish (FIN) AF: 0.0433 AC: 459 AN: 10610

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 67996

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.00791 Hom.: 16

Bravo AF: 0.0229

Asia WGS AF: 0.165 AC: 572 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Obesity (1)
-	-	1	Obesity due to pro-opiomelanocortin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.8
DANN	Benign	0.81
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: rs28930368; hg19: chr2-25384472; COSMIC: COSV53034960; COSMIC: COSV53034960;