NM_000939.4:c.289_297dupAGCAGCGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000939.4(POMC):c.289_297dupAGCAGCGGC(p.Gly99_Ala100insSerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 1,557,810 control chromosomes in the GnomAD database, including 5,307 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1657 hom., cov: 31)

Exomes 𝑓: 0.061 ( 3650 hom. )

Consequence

POMC
NM_000939.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.649

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 -16 ACMG points.

BP6

Variant 2-25161587-C-CGCCGCTGCT is Benign according to our data. Variant chr2-25161587-C-CGCCGCTGCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	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.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17200

AN:

151752

Hom.:

1655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0555

Gnomad ASJ

AF:

0.0874

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0538

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.0552

Gnomad OTH

AF:

0.0897

GnomAD2 exomes

AF:

0.0564

AC:

8677

AN:

153946

AF XY:

0.0554

show subpopulations

Gnomad AFR exome

AF:

0.240

Gnomad AMR exome

AF:

0.0358

Gnomad ASJ exome

AF:

0.0944

Gnomad EAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.0543

Gnomad NFE exome

AF:

0.0487

Gnomad OTH exome

AF:

0.0632

GnomAD4 exome

AF:

0.0608

AC:

85424

AN:

1405942

Hom.:

3650

Cov.:

AF XY:

0.0600

AC XY:

41686

AN XY:

694622

show subpopulations

African (AFR)

AF:

0.282

AC:

8910

AN:

31572

American (AMR)

AF:

0.0393

AC:

1447

AN:

36820

Ashkenazi Jewish (ASJ)

AF:

0.0950

AC:

2394

AN:

25194

East Asian (EAS)

AF:

0.000741

AC:

AN:

36442

South Asian (SAS)

AF:

0.0602

AC:

4831

AN:

80230

European-Finnish (FIN)

AF:

0.0575

AC:

2784

AN:

48386

Middle Eastern (MID)

AF:

0.108

AC:

611

AN:

5680

European-Non Finnish (NFE)

AF:

0.0558

AC:

60450

AN:

1083360

Other (OTH)

AF:

0.0681

AC:

3970

AN:

58258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4602

9203

13805

18406

23008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2480

4960

7440

9920

12400

<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:

0.113

AC:

17220

AN:

151868

Hom.:

1657

Cov.:

AF XY:

0.111

AC XY:

8251

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.270

AC:

11141

AN:

41252

American (AMR)

AF:

0.0554

AC:

846

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0874

AC:

303

AN:

3466

East Asian (EAS)

AF:

0.00174

AC:

AN:

5158

South Asian (SAS)

AF:

0.0591

AC:

285

AN:

4822

European-Finnish (FIN)

AF:

0.0538

AC:

571

AN:

10616

Middle Eastern (MID)

AF:

0.0822

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0552

AC:

3750

AN:

67964

Other (OTH)

AF:

0.0907

AC:

191

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

705

1410

2116

2821

3526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0390

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15472174) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Sep 26, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 10, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic Non-Syndromic Obesity

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Obesity due to pro-opiomelanocortin deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

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