rs28932470

Variant names:

• chr2-25161727-T-C
• rs28932470
• NM_000939.4:c.158A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-25161727-T-C
• chr2-25161727-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000939.4(POMC):​c.158A>G​(p.Asp53Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,594,094 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D53A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.94
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010462016).
• BP6: Variant 2-25161727-T-C is Benign according to our data. Variant chr2-25161727-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 335357.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00202 (307/152050) while in subpopulation AFR AF = 0.00545 (226/41478). AF 95% confidence interval is 0.00487. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,SD,AD gene

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.158A>G	p.Asp53Gly	missense	Exon 3 of 3	NP_000930.1
	POMC	NM_001035256.3		c.158A>G	p.Asp53Gly	missense	Exon 4 of 4	NP_001030333.1
	POMC	NM_001319204.2		c.158A>G	p.Asp53Gly	missense	Exon 4 of 4	NP_001306133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.158A>G	p.Asp53Gly	missense	Exon 3 of 3	ENSP00000379170.2
	POMC	ENST00000405623.5	TSL:1	c.158A>G	p.Asp53Gly	missense	Exon 3 of 3	ENSP00000384092.1
	POMC	ENST00000264708.7	TSL:2	c.158A>G	p.Asp53Gly	missense	Exon 4 of 4	ENSP00000264708.3

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 305 AN: 151938 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000899 AC: 188 AN: 209074 AF XY: 0.000812

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000556

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.000472 AC: 680 AN: 1442044 Hom.: 2 Cov.: 33 AF XY: 0.000441 AC XY: 316 AN XY: 715776

African (AFR) AF: 0.00572 AC: 188 AN: 32880

American (AMR) AF: 0.00292 AC: 125 AN: 42804

Ashkenazi Jewish (ASJ) AF: 0.000389 AC: 10 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38476

South Asian (SAS) AF: 0.0000482 AC: 4 AN: 82922

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50502

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5684

European-Non Finnish (NFE) AF: 0.000240 AC: 265 AN: 1103526

Other (OTH) AF: 0.00136 AC: 81 AN: 59540

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152050 Hom.: 0 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74342

African (AFR) AF: 0.00545 AC: 226 AN: 41478

American (AMR) AF: 0.00307 AC: 47 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67926

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000668 Hom.: 1

Bravo AF: 0.00254

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00193 AC: 7

ESP6500EA AF: 0.000410 AC: 3

ExAC AF: 0.000856 AC: 100

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Obesity (1)
-	-	1	Obesity due to pro-opiomelanocortin deficiency (1)
-	1	-	Obesity;C1857854:Obesity due to pro-opiomelanocortin deficiency (1)
-	-	1	POMC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.41
Sift	Benign	0.059	T
Sift4G	Benign	0.16	T
Polyphen		0.29	B
Vest4		0.31
MVP		0.88
MPC		0.39
ClinPred		0.021	T
GERP RS		2.7
Varity_R		0.24
gMVP		0.62
Mutation Taster		=98/2	polymorphism

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: rs28932470; hg19: chr2-25384596;