NM_000939.4:c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.
The NM_000939.4(POMC):c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC(p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000724 in 151,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000020 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
POMC
NM_000939.4 conservative_inframe_insertion
NM_000939.4 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.649
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 deficiencyInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
- inherited obesityInheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| POMC | NM_000939.4 | MANE Select | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 3 of 3 | NP_000930.1 | ||
| POMC | NM_001035256.3 | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 4 of 4 | NP_001030333.1 | |||
| POMC | NM_001319204.2 | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 4 of 4 | NP_001306133.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| POMC | ENST00000395826.7 | TSL:2 MANE Select | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 3 of 3 | ENSP00000379170.2 | ||
| POMC | ENST00000405623.5 | TSL:1 | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 3 of 3 | ENSP00000384092.1 | ||
| POMC | ENST00000264708.7 | TSL:2 | c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC | p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly | conservative_inframe_insertion | Exon 4 of 4 | ENSP00000264708.3 |
Frequencies
GnomAD3 genomes 0.0000725 AC: 11AN: 151776Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
11
AN:
151776
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.0000195 AC: 3AN: 153946 AF XY: 0.0000239 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
153946
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000199 AC: 28AN: 1406036Hom.: 0 Cov.: 33 AF XY: 0.0000216 AC XY: 15AN XY: 694676 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
28
AN:
1406036
Hom.:
Cov.:
33
AF XY:
AC XY:
15
AN XY:
694676
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
6
AN:
31600
American (AMR)
AF:
AC:
0
AN:
36824
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25194
East Asian (EAS)
AF:
AC:
0
AN:
36442
South Asian (SAS)
AF:
AC:
16
AN:
80238
European-Finnish (FIN)
AF:
AC:
0
AN:
48394
Middle Eastern (MID)
AF:
AC:
1
AN:
5684
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1083400
Other (OTH)
AF:
AC:
1
AN:
58260
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000216493), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.384
Heterozygous variant carriers
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Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.0000724 AC: 11AN: 151892Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74264 show subpopulations
GnomAD4 genome
AF:
AC:
11
AN:
151892
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
74264
show subpopulations
African (AFR)
AF:
AC:
10
AN:
41270
American (AMR)
AF:
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3466
East Asian (EAS)
AF:
AC:
0
AN:
5158
South Asian (SAS)
AF:
AC:
1
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67970
Other (OTH)
AF:
AC:
0
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
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Age
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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