NM_000939.4:c.280_297dupAGCAGCGGCAGCAGCGGC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000939.4(POMC):c.280_297dupAGCAGCGGCAGCAGCGGC(p.Gly99_Ala100insSerSerGlySerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,557,926 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

POMC
NM_000939.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

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: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000889 (135/151892) while in subpopulation AMR AF = 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.280_297dupAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.280_297dupAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.280_297dupAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.280_297dupAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGly	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.280_297dupAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.000889

AC:

135

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000422

AC:

AN:

153946

AF XY:

0.000395

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.000707

Gnomad ASJ exome

AF:

0.000957

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000128

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000358

AC:

504

AN:

1406034

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

264

AN XY:

694674

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

31600

American (AMR)

AF:

0.00133

AC:

AN:

36824

Ashkenazi Jewish (ASJ)

AF:

0.00143

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36442

South Asian (SAS)

AF:

0.000399

AC:

AN:

80238

European-Finnish (FIN)

AF:

0.0000827

AC:

AN:

48392

Middle Eastern (MID)

AF:

0.00281

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.000231

AC:

250

AN:

1083398

Other (OTH)

AF:

0.00113

AC:

AN:

58262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000889

AC:

135

AN:

151892

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

41270

American (AMR)

AF:

0.00164

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67970

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000439

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 04, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.280_297dup, results in the insertion of 6 amino acid(s) of the POMC protein (p.Ser94_Gly99dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs10654394, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with extreme obesity but a second variant was not observed (PMID: 9768693). This variant is also known as the 18bp insertion between codon 73 and 74. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity

Uncertain:1

Feb 18, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inherited obesity

Uncertain:1

Mar 25, 2024

Baylor Genetics

Significance:Uncertain significance

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

(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