Genetic Variant MC3R:p.Ile50Thr (chr20-56248992-T-C) – ACMG Classification: Likely_benign (-5 pts)

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.98

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2878846).

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC3R	NM_019888.3 link	c.149T>C	p.Ile50Thr	missense_variant	Exon 1 of 1	ENST00000243911.2	NP_063941.3	P41968

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC3R	ENST00000243911.2 link	c.149T>C	p.Ile50Thr	missense_variant	Exon 1 of 1	6	NM_019888.3	ENSP00000243911.2		P41968

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000956

AC:

AN:

251068

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135684

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000275

AC:

402

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000347

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000177

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MC3R-related disorder

Uncertain:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided

Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 50 of the MC3R protein (p.Ile50Thr). This variant is present in population databases (rs370084821, gnomAD 0.03%). This missense change has been observed in individual(s) with obesity (PMID: 19091795, 29970488). This variant is also known as c.260T>C , p.Ile87Thr . ClinVar contains an entry for this variant (Variation ID: 2634244). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects MC3R function (PMID: 22884546, 25798062). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

M_CAP

Benign

0.017

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.16

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.058

Vest4

0.32

MVP

0.69

MPC

0.27

ClinPred

0.20

GERP RS

3.9

Varity_R

0.30

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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