rs121913560

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005912.3(MC4R):c.508A>G(p.Ile170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 1.40

Variant links:

Genes affected

MC4R (HGNC:6932): (melanocortin 4 receptor) The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity. [provided by RefSeq, Jan 2010]

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23309362).

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.508A>G	p.Ile170Val	missense_variant	1/1	ENST00000299766.5	NP_005903.2	P32245

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MC4R	ENST00000299766.5 linkuse as main transcript	c.508A>G	p.Ile170Val	missense_variant	1/1	6	NM_005912.3	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1 linkuse as main transcript	n.113+42497T>C		intron_variant
ENSG00000285681	ENST00000658928.1 linkuse as main transcript	n.156+42497T>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251336

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000965

AC:

141

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000190

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.000238

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Imperial College London Diabetes Centre, Mubadala Healthcare	May 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the MC4R protein (p.Ile170Val). This variant is present in population databases (rs121913560, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of MC4R-related obesity (PMID: 10903341, 11487744, 18559663, 19011902, 26788538, 31751304, 31980526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14323). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 10903341, 12690102, 12959994, 16752916, 19011902, 25332687, 29736023). 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. -

MC4R-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The MC4R c.508A>G variant is predicted to result in the amino acid substitution p.Ile170Val. This variant has been reported in several individuals with severe obesity; however, its role in pathogenesis has been controversial. It was originally described in two apparently unrelated patients with a BMI >30, and was found to marginally compromise receptor surface localization and function in vitro (Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier. 2006. PubMed ID: 16507637). Since then a significant number of studies have shown that it imparts no change to cell surface expression, ligand binding, or cAMP signaling (See for example, He. 2014. PubMed ID: 25332687; Clément et al. 2018. PubMed ID: 29736023, Supp Table 5). It was found to be a common variant among South African individuals with obesity (2%; n=9;); however, a match control cohort was not included (Logan. 2016. PubMed ID: 26788538). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD. Taken together, 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

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.072

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.40

Sift

Uncertain

0.012

Sift4G

Benign

0.16

Polyphen

0.81

Vest4

0.73

MVP

0.64

MPC

0.016

ClinPred

0.060

GERP RS

3.4

Varity_R

0.28

gMVP

0.77

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