chr18-60371970-G-A

Position:

chr18-60371970-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3PP5BS2_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).

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

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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 id is 14336.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Uncertain_significance=2, Pathogenic=1}. Variant chr18-60371970-G-A is described in Lovd as [Pathogenic].

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/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.380C>T	p.Ser127Leu	missense_variant	1/1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
MC4R	ENST00000299766.5 linkuse as main transcript	c.380C>T	p.Ser127Leu	missense_variant	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42625G>A		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42625G>A		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251366

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135868

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000283

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:5Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 29, 2023	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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	The S127L variant in the MC4R gene has been reported in individuals with obesity (Lubrano-Berthelier et al., 2003; Rovite et al., 2014). Functional assays showed S127L has decreased membrane trafficking and functional activity (Rovite et al., 2014). The S127L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S127L variant is a non-conservative amino acid substitution, which occurs within the Transmembrane 3 domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (D126Y) has been reported in the Human Gene Mutation Database in association with obesity (Stenson et al., 2014), supporting the functional importance of this region of the protein. The S127L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 12, 2022	_x000D_ Criteria applied: PS3, PS4_MOD -

Obesity

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	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. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MC4R c.380C>T (p.Ser127Leu) variant has been identified in a heterozygous state in six individuals and in a compound heterozygous state in nine individuals with obesity with a known polymorphism in the MC4R gene (Hinney et al. 2003; Valli-Jaakola et al. 2004; Hainerova et al. 2007; Calton et al. 2009; Santoro et al. 2009; Nowacka-Woszuk et al. 2011; Albuquerque et al. 2014; Rovite et al. 2014). The variant is also found in five unaffected individuals, including two that carried the variant in a compound heterozygous state with a common MC4R polymorphism (Nowacka-Woszuk et al. 2011; Rouskas et al. 2012; Stanikova et al. 2015). Functional studies for the p.Ser127Leu variant revealed a constituitively active receptor (Hinney et al. 2003; Srinivasan et al. 2007; Mo et al. 2013; ), which conflicts with functional studies showing decreased cell surface expression (Rovite et al. 2014), impaired signaling (Valli-Jaakola et al. 2004), and altered alpha-MSH activation of the receptor (Lubrano-Berthelier et al. 2003). The p.Ser127eu variant is reported at a frequency of 0.00052 in the Latino population of the Exome Aggregation Consortium. Based on the conflicting evidence from the literature, the p.Ser127Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Obesity due to melanocortin 4 receptor deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2022

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

MC4R-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2024

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

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

MutationTaster

Benign

1.0

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

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

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