rs80326661

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.0140

Publications

11 publications found

Variant links:

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

POMC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.641A>G	p.Glu214Gly	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.641A>G	p.Glu214Gly	missense_variant	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.641A>G	p.Glu214Gly	missense_variant	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.641A>G	p.Glu214Gly	missense_variant	Exon 3 of 3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.641A>G	p.Glu214Gly	missense_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

793

AN:

151424

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00683

AC XY:

4960

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

33466

American (AMR)

AF:

0.000918

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00464

AC:

121

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

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:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00813

AC:

9039

AN:

1111292

Other (OTH)

AF:

0.00434

AC:

262

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

671

1342

2012

2683

3354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00523

AC:

793

AN:

151544

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

354

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

41256

American (AMR)

AF:

0.000852

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00405

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.000837

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00825

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00919

AC:

623

AN:

67802

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00710

Hom.:

Bravo

AF:

0.00411

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00550

AC:

668

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00802

EpiControl

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POMC: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with obesity in published literature, although the variant did not segregate with disease in one family and was also found at a higher frequency in controls in another study (also reported as p.(Glu188Gly) using alternate nomenclature; PMID: 9768693, 12068494, 24890885, 29970488); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970488, 9768693, 12068494, 24890885) -

not specified

Benign:1

Nov 25, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POMC-related disorder

Benign:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Obesity

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.2

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.69

D;D;D;D;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.57

T;.;.;.;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.0090

T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.7

L;L;L;L;.

PhyloP100

-0.014

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.2

D;D;D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.033

D;D;D;D;D

Sift4G

Benign

0.21

T;T;T;T;.

Polyphen

0.54

P;P;P;P;.

Vest4

0.078

MVP

0.82

MPC

0.35

ClinPred

0.020

GERP RS

-2.6

Varity_R

0.060

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over