20-56249134-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_019888.3(MC3R):c.291G>A(p.Met97Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00028 in 1,614,140 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 4 hom. )

Consequence

MC3R
NM_019888.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64

Variant links:

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]

MC3R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010233045).

BS2

High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC3R	NM_019888.3 linkuse as main transcript	c.291G>A	p.Met97Ile	missense_variant	1/1	ENST00000243911.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC3R	ENST00000243911.2 linkuse as main transcript	c.291G>A	p.Met97Ile	missense_variant	1/1		NM_019888.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000601

AC:

151

AN:

251222

Hom.:

AF XY:

0.000854

AC XY:

116

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00483

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000299

AC:

437

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

330

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

Jan 19, 2024

The MC3R c.291G>A variant is predicted to result in the amino acid substitution p.Met97Ile. This variant has been identified in individuals with childhood obesity (described as Met134Ile, Lee et al. 2007. PubMed ID: 17639020). Functional analyses of the p.Met97Ile variant showed it had decreased maximal binding, but displayed similar signaling properties as wild-type MC3R (described as M134I, Yang and Tao. 2012. PubMed ID: 22884546). This variant was also shown to increase cAMP activity, but had no significant effect on pERK1/2 levels (described as M134I, Yang et al. 2015. PubMed ID: 25798062). This variant is reported in 0.48% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be a cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.024

Eigen

Benign

0.045

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0048

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.52

MutationTaster

Benign

0.83

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.85

REVEL

Benign

0.21

Sift

Benign

0.33

Sift4G

Benign

0.73

Vest4

0.58

MVP

0.66

MPC

0.29

ClinPred

0.093

GERP RS

4.8

Varity_R

0.21

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over