rs13447331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PP2PP3PP5BS2_Supporting

The NM_005912.3(MC4R):c.380C>T(p.Ser127Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S127P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:2

Conservation

PhyloP100: 10.0

Publications

50 publications found

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 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

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a transmembrane_region Helical; Name=3 (size 21) in uniprot entity MC4R_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

PP5

Variant 18-60371970-G-A is Pathogenic according to our data. Variant chr18-60371970-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14336.

BS2

High AC in GnomAd4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC4R	NM_005912.3 link	c.380C>T	p.Ser127Leu	missense_variant	Exon 1 of 1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MC4R	ENST00000299766.5 link	c.380C>T	p.Ser127Leu	missense_variant	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1 link	n.113+42625G>A		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1 link	n.156+42625G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000171

AC:

AN:

251366

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000120

AC:

175

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000113

AC:

126

AN:

1112006

Other (OTH)

AF:

0.000149

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a single heterozygous variant and in patients with a second variant in the MC4R gene in the published literature in association with obesity (PMID: 24611737, 24385306, 12499395, 26238496, 40231439, 30926952); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect leading to decreased membrane trafficking and functional activity (PMID: 12499395, 24385306); This variant is associated with the following publications: (PMID: 24385306, 12499395, 26238496, 17357083, 23791567, 16752916, 18559663, 17628007, 19091795, 23146882, 20696697, 12970296, 14764818, 19298524, 22447289, 16083993, 26047380, 35562395, 17590021, 31447099, 30048591, 37040537, 38528040, 34045736, 32059383, 32952152, 35801948, 24611737, 30926952, 37601970, 40231439, 37025415) -

Aug 29, 2018

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease in genotyped family members (p < 0.05), and data are from multiple families. One de novo case with parental identity confirmed. -

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 127 of the MC4R protein (p.Ser127Leu). This variant is present in population databases (rs13447331, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal dominant severe obesity (PMID: 12499395, 12970296, 14764818, 18559663, 24385306, 24611737, 26238496, 30926952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14336). 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: 12970296, 14764818, 22447289, 24385306). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:4

Feb 25, 2022

Institute of Human Genetics, Heidelberg University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 09, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PS3, PS4_MOD -

Obesity

Pathogenic:2

May 25, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.380C>T (p.Ser127Leu) variant in the MC4R gene has previously been reported in multiple patients presenting with obesity [PMID 12499395, 24385306, 18559663, 14764818, 26047380]. The variant was also detected in one lean individual, the mother of the obese proband, indicating possible incomplete penetrance [PMID 26047380]. Functional assays showed that the receptor displayed high constitutive activity [PMID 19298524, 12970296]. However, cell surface expression level of the p.Ser127Leu mutant was decreased by about half of wild type [PMID 19298524, 24385306]. Thus, the mechanism of pathogenicity for this variant in unclear at this time. Serine at amino acid position 127 of the MC4R protein is highly conserved in mammals. This variant has been observed in 20 heterozygous individuals from the ExAC database (http://exac.broadinstitute.org/variant/18-58039203-G-A). While not validated for clinical use, the computer-based algorithms SIFT and Polyphen2 predict this p.Ser127Leu change to be deleterious. It is thus interpreted as a likely pathogenic variant. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Ser127Leu variant in MC4R has been reported in 30 individuals (including 3 German, 3 Latvian, 2 Polish, 2 Iberian, 2 Finnish, 1 Slovak and 1 Czech individuals) who are overweight or have Obesity (PMID: 14764818, 17579204, 12499395, 23146882, 12970296, 24385306, 26047380, 24611737, 18559663, 19284607, 21404042, 19091795, 17357083), and has been identified in 0.1157% (12/10370) of Ashkenazi Jewish chromosomes and 0.02090% (27/129176) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447331). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 14336). In vitro functional studies provide some evidence that the p.Ser127Leu variant may impact protein function (PMID: 14764818, 12499395, 16752916, 12970296, 23791567, 19298524). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_moderate (Richards 2015). -

Obesity due to melanocortin 4 receptor deficiency

Pathogenic:1

Mar 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

MC4R-related disorder

Pathogenic:1

May 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MC4R c.380C>T variant is predicted to result in the amino acid substitution p.Ser127Leu. This variant has been identified in the heterozygous state in multiple individuals with obesity (Lubrano-Berthelier et al. 2004. PubMed ID: 15126516; Stutzmann et al. 2008. PubMed ID: 18559663; Stankiova et al. 2015. PubMed ID: 26047380). However, it has also been described in lean individuals (Stankiova et al. 2015. PubMed ID: 26047380; Rouskas et al. 2012. PubMed ID: 22447289). Multiple functional studies testing this variant have shown that it alters the protein’s biophysical properties and cell surface expression (for a review see Fan and Tao. 2009. PubMed ID: 19298524). This variant is interpreted as likely pathogenic in ClinVar by the vast majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/14336/). Based on the collective information, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.87

MutationAssessor

Pathogenic

3.0

PhyloP100

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.53

Sift

Benign

0.13

Sift4G

Benign

0.43

Polyphen

1.0

Vest4

0.94

MVP

0.83

MPC

0.10

ClinPred

0.22

GERP RS

5.7

Varity_R

0.52

gMVP

0.91

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over