2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT

Variant names:

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly	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.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.0000725

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000195

AC:

AN:

153946

AF XY:

0.0000239

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000199

AC:

AN:

1406036

Hom.:

Cov.:

AF XY:

0.0000216

AC XY:

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:

0.000190

AC:

AN:

31600

American (AMR)

AF:

0.00

AC:

AN:

36824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36442

South Asian (SAS)

AF:

0.000199

AC:

AN:

80238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48394

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000369

AC:

AN:

1083400

Other (OTH)

AF:

0.0000172

AC:

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

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41270

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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

ClinVar

Not reported in ClinVar

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

Computational scores

Splicing

Publications

Other links and lift over