rs80326661

Variant names:

• chr2-25161244-T-C
• rs80326661
• NM_000939.4:c.641A>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.641A>G​(p.Glu214Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,611,820 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E214E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (38 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0140
• Publications: 11 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=0.008984923).
• BP6: Variant 2-25161244-T-C is Benign according to our data. Variant chr2-25161244-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211936.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00523 (793/151544) while in subpopulation NFE AF = 0.00919 (623/67802). AF 95% confidence interval is 0.00859. There are 7 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.641A>G	p.Glu214Gly	missense	Exon 3 of 3	NP_000930.1
	POMC	NM_001035256.3		c.641A>G	p.Glu214Gly	missense	Exon 4 of 4	NP_001030333.1
	POMC	NM_001319204.2		c.641A>G	p.Glu214Gly	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.641A>G	p.Glu214Gly	missense	Exon 3 of 3	ENSP00000379170.2
	POMC	ENST00000405623.5	TSL:1	c.641A>G	p.Glu214Gly	missense	Exon 3 of 3	ENSP00000384092.1
	POMC	ENST00000264708.7	TSL:2	c.641A>G	p.Glu214Gly	missense	Exon 4 of 4	ENSP00000264708.3

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 793 AN: 151424 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00405

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000836

Gnomad FIN AF: 0.00825

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00542 AC: 1348 AN: 248690 AF XY: 0.00542

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.00883

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00695 AC: 10154 AN: 1460276 Hom.: 38 Cov.: 32 AF XY: 0.00683 AC XY: 4960 AN XY: 726312

African (AFR) AF: 0.000867 AC: 29 AN: 33466

American (AMR) AF: 0.000918 AC: 41 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 121 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00130 AC: 112 AN: 86116

European-Finnish (FIN) AF: 0.0103 AC: 547 AN: 52878

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00813 AC: 9039 AN: 1111292

Other (OTH) AF: 0.00434 AC: 262 AN: 60328

GnomAD4 genome AF: 0.00523 AC: 793 AN: 151544 Hom.: 7 Cov.: 33 AF XY: 0.00478 AC XY: 354 AN XY: 74076

African (AFR) AF: 0.00107 AC: 44 AN: 41256

American (AMR) AF: 0.000852 AC: 13 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00405 AC: 14 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000837 AC: 4 AN: 4780

European-Finnish (FIN) AF: 0.00825 AC: 87 AN: 10548

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

European-Non Finnish (NFE) AF: 0.00919 AC: 623 AN: 67802

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00710 Hom.: 3

Bravo AF: 0.00411

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.00550 AC: 668

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	not specified (1)
-	-	1	Obesity (1)
-	-	1	POMC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.2
DANN	Benign	0.96
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.014
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.31
Sift	Benign	0.033	D
Sift4G	Benign	0.21	T
Polyphen		0.54	P
Vest4		0.078
MVP		0.82
MPC		0.35
ClinPred		0.020	T
GERP RS		-2.6
Varity_R		0.060
gMVP		0.19
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: rs80326661; hg19: chr2-25384113; COSMIC: COSV104585116; COSMIC: COSV104585116;