chr20-56248992-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_019888.3(MC3R):c.149T>C(p.Ile50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000266 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
MC3R
NM_019888.3 missense
NM_019888.3 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 4.98
Genes affected
MC3R (HGNC:6931): (melanocortin 3 receptor) This gene encodes a G-protein-coupled receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone that is expressed in tissues other than the adrenal cortex and melanocytes. This gene maps to the same region as the locus for benign neonatal epilepsy. Mice deficient for this gene have increased fat mass despite decreased food intake, suggesting a role for this gene product in the regulation of energy homeostasis. Mutations in this gene are associated with a susceptibility to obesity in humans. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2878846).
BS2
?
High AC in GnomAd at 27 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC3R | NM_019888.3 | c.149T>C | p.Ile50Thr | missense_variant | 1/1 | ENST00000243911.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC3R | ENST00000243911.2 | c.149T>C | p.Ile50Thr | missense_variant | 1/1 | NM_019888.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000956 AC: 24AN: 251068Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135684
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GnomAD4 exome AF: 0.000275 AC: 402AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.000264 AC XY: 192AN XY: 727244
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GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MC3R-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 08, 2023 | The MC3R c.149T>C variant is predicted to result in the amino acid substitution p.Ile50Thr. This variant has been reported as a heterozygous variant of uncertain significance in three different studies of obesity (Cooiman et al. 2019. PubMed ID: 31650404, Table S3; Kleinendorst et al. 2018. PubMed ID: 29970488, Table 2; Calton et al. 2009. PubMed ID: 19091795, Table 1, described as c.260T>C, Ile87Thr). In vitro studies provide conflicting results on this variant's impact on protein function (reported as I87T in Yang et al. 2012. PubMed ID: 22884546; Table S2, Duckett et al. 2023. PubMed ID: 37339320). Another study indicates there is no statistically significant difference in median BMI for carriers of this variant compared to matched controls (Melvin et al. 2020. https://doi.org/10.1210/jendso/bvaa046.2097). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
T
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at