chr20-56249115-A-G
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_019888.3(MC3R):c.272A>G(p.Asn91Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 2 hom. )
Consequence
MC3R
NM_019888.3 missense
NM_019888.3 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 9.01
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 -4 ACMG points.
BS2
?
High AC in GnomAd at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC3R | NM_019888.3 | c.272A>G | p.Asn91Ser | missense_variant | 1/1 | ENST00000243911.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC3R | ENST00000243911.2 | c.272A>G | p.Asn91Ser | missense_variant | 1/1 | NM_019888.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152166Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
8
AN:
152166
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: 0.0000717 AC: 18AN: 251188Hom.: 2 AF XY: 0.0000884 AC XY: 12AN XY: 135756
GnomAD3 exomes
AF:
AC:
18
AN:
251188
Hom.:
AF XY:
AC XY:
12
AN XY:
135756
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: 0.0000363 AC: 53AN: 1461886Hom.: 2 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727244
GnomAD4 exome
AF:
AC:
53
AN:
1461886
Hom.:
Cov.:
33
AF XY:
AC XY:
32
AN XY:
727244
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: 0.0000525 AC: 8AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74460
GnomAD4 genome
?
AF:
AC:
8
AN:
152284
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74460
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:
ExAC
?
AF:
AC:
10
EpiCase
AF:
EpiControl
AF:
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 | May 23, 2023 | The MC3R c.272A>G variant is predicted to result in the amino acid substitution p.Asn91Ser. This variant has been reported in two individuals with obesity using alternate nomenclature (383A>G, N128S; Zegers et al. 2011. PubMed ID: 20539302; Zegers et al. 2013. PubMed ID: 23264184). Functional analysis of this variant has been inconclusive. It does not appear to alter plasma membrane localization (Zegers et al. 2011. PubMed ID: 20539302), and alpha-MSH-stimulated cAMP signaling is mildly reduced or unchanged (Zegers et al. 2011. PubMed ID: 20539302; Yang et al. 2015. PubMed ID: 25798062). However, alpha-MSH-stimulated pERK 1/2 signaling is significantly reduced (Yang et al. 2015. PubMed ID: 25798062). The physiological consequences of these data are unknown. 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
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Vest4
MVP
MPC
ClinPred
T
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