20-56248977-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_019888.3(MC3R):c.134T>C(p.Phe45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,614,062 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
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 0 hom. )
Consequence
MC3R
NM_019888.3 missense
NM_019888.3 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 7.82
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.938
BS2
?
High AC in GnomAd at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC3R | NM_019888.3 | c.134T>C | p.Phe45Ser | missense_variant | 1/1 | ENST00000243911.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC3R | ENST00000243911.2 | c.134T>C | p.Phe45Ser | missense_variant | 1/1 | NM_019888.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152184Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
22
AN:
152184
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 250956Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135632
GnomAD3 exomes
AF:
AC:
17
AN:
250956
Hom.:
AF XY:
AC XY:
10
AN XY:
135632
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000405 AC: 592AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.000382 AC XY: 278AN XY: 727242
GnomAD4 exome
AF:
AC:
592
AN:
1461878
Hom.:
Cov.:
33
AF XY:
AC XY:
278
AN XY:
727242
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74342
GnomAD4 genome
?
AF:
AC:
22
AN:
152184
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
74342
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
3
ALSPAC
AF:
AC:
2
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
3
ExAC
?
AF:
AC:
6
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Obesity Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 20, 2021 | ACMG categories: PP3 - |
MC3R-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 04, 2024 | The MC3R c.134T>C variant is predicted to result in the amino acid substitution p.Phe45Ser. This variant has been reported in the literature, with functional studies supporting an effect on the protein (alternate nomenclature Phe82Ser, Calton et al. 2009. PubMed ID: 19091795; Yang et al. 2015. PubMed ID: 25798062; Lam et al. 2021. PubMed ID: 34732894). However, available case-control data indicate this variant is not associated with obesity. This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, 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
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at