2-25161169-C-T
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000939.4(POMC):c.716G>A(p.Gly239Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000939.4 missense
Scores
Clinical Significance
Conservation
Publications
- 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
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POMC | NM_000939.4 | c.716G>A | p.Gly239Asp | missense_variant | Exon 3 of 3 | ENST00000395826.7 | NP_000930.1 | |
POMC | NM_001035256.3 | c.716G>A | p.Gly239Asp | missense_variant | Exon 4 of 4 | NP_001030333.1 | ||
POMC | NM_001319204.2 | c.716G>A | p.Gly239Asp | missense_variant | Exon 4 of 4 | NP_001306133.1 | ||
POMC | NM_001319205.2 | c.716G>A | p.Gly239Asp | missense_variant | Exon 3 of 3 | NP_001306134.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461632Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727132 show subpopulations
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 239 of the POMC protein (p.Gly239Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POMC-related conditions. ClinVar contains an entry for this variant (Variation ID: 2079912). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POMC protein function with a positive predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at