chr2-25161018-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000939.4(POMC):​c.*63C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,607,892 control chromosomes in the GnomAD database, including 25,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2078 hom., cov: 33)
Exomes 𝑓: 0.17 ( 23535 hom. )

Consequence

POMC
NM_000939.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.880
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 2-25161018-G-A is Benign according to our data. Variant chr2-25161018-G-A is described in ClinVar as [Benign]. Clinvar id is 335352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POMCNM_000939.4 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 3/3 ENST00000395826.7
POMCNM_001035256.3 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 4/4
POMCNM_001319204.2 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 4/4
POMCNM_001319205.2 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POMCENST00000395826.7 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 3/32 NM_000939.4 P1
POMCENST00000405623.5 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 3/31 P1
POMCENST00000264708.7 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 4/42 P1
POMCENST00000380794.5 linkuse as main transcriptc.*63C>T 3_prime_UTR_variant 4/42 P1

Frequencies

GnomAD3 genomes
AF:
0.154
AC:
23472
AN:
152192
Hom.:
2074
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.125
Gnomad AMI
AF:
0.246
Gnomad AMR
AF:
0.164
Gnomad ASJ
AF:
0.228
Gnomad EAS
AF:
0.0175
Gnomad SAS
AF:
0.0859
Gnomad FIN
AF:
0.0935
Gnomad MID
AF:
0.266
Gnomad NFE
AF:
0.188
Gnomad OTH
AF:
0.178
GnomAD4 exome
AF:
0.173
AC:
252437
AN:
1455582
Hom.:
23535
Cov.:
32
AF XY:
0.172
AC XY:
124253
AN XY:
723870
show subpopulations
Gnomad4 AFR exome
AF:
0.121
Gnomad4 AMR exome
AF:
0.115
Gnomad4 ASJ exome
AF:
0.225
Gnomad4 EAS exome
AF:
0.0101
Gnomad4 SAS exome
AF:
0.0917
Gnomad4 FIN exome
AF:
0.101
Gnomad4 NFE exome
AF:
0.192
Gnomad4 OTH exome
AF:
0.167
GnomAD4 genome
AF:
0.154
AC:
23484
AN:
152310
Hom.:
2078
Cov.:
33
AF XY:
0.149
AC XY:
11119
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.125
Gnomad4 AMR
AF:
0.164
Gnomad4 ASJ
AF:
0.228
Gnomad4 EAS
AF:
0.0175
Gnomad4 SAS
AF:
0.0855
Gnomad4 FIN
AF:
0.0935
Gnomad4 NFE
AF:
0.188
Gnomad4 OTH
AF:
0.176
Alfa
AF:
0.162
Hom.:
292
Bravo
AF:
0.158
Asia WGS
AF:
0.0560
AC:
198
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJun 19, 2021This variant is associated with the following publications: (PMID: 14513068, 23028917, 23315997) -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Obesity Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Obesity due to pro-opiomelanocortin deficiency Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
5.1
DANN
Benign
0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1042571; hg19: chr2-25383887; API