rs121913560

Variant names:

• chr18-60371842-T-C
• rs121913560
• NM_005912.3:c.508A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-60371842-T-C
• chr18-60371842-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1 PP2 PP5 BP4 BS1_Supporting BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 1.40
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• inherited obesity

  Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
• obesity due to melanocortin 4 receptor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285681 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_005912.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.0099 (below the threshold of 3.09). Trascript score misZ: 0.30396 (below the threshold of 3.09). GenCC associations: The gene is linked to obesity due to melanocortin 4 receptor deficiency, inherited obesity.
• PP5: Variant 18-60371842-T-C is Pathogenic according to our data. Variant chr18-60371842-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14323.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23309362). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000965 (141/1461868) while in subpopulation AFR AF = 0.00149 (50/33480). AF 95% confidence interval is 0.00116. There are 0 homozygotes in GnomAdExome4. There are 64 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.508A>G	p.Ile170Val	missense	Exon 1 of 1	NP_005903.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	ENST00000299766.5	TSL:6 MANE Select	c.508A>G	p.Ile170Val	missense	Exon 1 of 1	ENSP00000299766.3
	ENSG00000285681	ENST00000650201.1		n.113+42497T>C		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+42497T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152150 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000796 AC: 20 AN: 251336 AF XY: 0.0000663

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 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.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727236

African (AFR) AF: 0.00149 AC: 50 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112008

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74432

African (AFR) AF: 0.000554 AC: 23 AN: 41538

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:3 Uncertain:1

Nov 11, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 01, 2020

Imperial College London Diabetes Centre, Mubadala Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:2

Nov 05, 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 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Apr 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies show conflicting evidence regarding the potential damaging effect of this variant (PMID: 19011902, 12959994, 10903341, 12690102); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 22995991, 10903341, 12959994, 12690102, 17628007, 16752916, 19011902, 18559663, 25332687, 26788538, 16507637, 31751304, 31980526, 29736023, 11487744, 38974580, 37329217, 35095762)

MC4R-related disorder Uncertain:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.012	D
Sift4G	Benign	0.16	T
Polyphen		0.81	P
Vest4		0.73
MVP		0.64
MPC		0.016
ClinPred		0.060	T
GERP RS		3.4
Varity_R		0.28
gMVP		0.77
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913560; hg19: chr18-58039075;