18-60371437-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PM5PP2PP3PP5BS2_Supporting

The NM_005912.3(MC4R):​c.913C>T​(p.Arg305Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,068 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. R305Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

5
12
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 4.54
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005912.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr18-60371436-C-T is described in Lovd as [Pathogenic].
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 inherited obesity, obesity due to melanocortin 4 receptor deficiency.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833
PP5
Variant 18-60371437-G-A is Pathogenic according to our data. Variant chr18-60371437-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586138.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3, Pathogenic=1}.
BS2
High AC in GnomAd4 at 8 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
MC4RNM_005912.3 linkc.913C>T p.Arg305Trp missense_variant Exon 1 of 1 ENST00000299766.5 NP_005903.2 P32245

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MC4RENST00000299766.5 linkc.913C>T p.Arg305Trp missense_variant Exon 1 of 1 6 NM_005912.3 ENSP00000299766.3 P32245
ENSG00000285681ENST00000650201.1 linkn.113+42092G>A intron_variant Intron 1 of 3
ENSG00000285681ENST00000658928.1 linkn.156+42092G>A intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000278
AC:
7
AN:
251396
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
AC:
1
AN:
33480
Gnomad4 AMR exome
AF:
0.0000894
AC:
4
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.0000232
AC:
2
AN:
86252
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53418
Gnomad4 NFE exome
AF:
0.0000162
AC:
18
AN:
1111932
Gnomad4 Remaining exome
AF:
0.0000497
AC:
3
AN:
60394
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000525
AC:
8
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000120
AC:
0.000120325
AN:
0.000120325
Gnomad4 AMR
AF:
0.000131
AC:
0.000130856
AN:
0.000130856
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000207297
AN:
0.000207297
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.00
AC:
0
AN:
0
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000679
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:3Uncertain:1
Apr 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 305 of the MC4R protein (p.Arg305Trp). This variant is present in population databases (rs549442687, gnomAD 0.01%). This missense change has been observed in individual(s) with obesity (PMID: 12851297, 16507637, 18559663, 20696697, 29970488). ClinVar contains an entry for this variant (Variation ID: 586138). 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 have shown that this missense change affects MC4R function (PMID: 16507637, 18559663, 20696697). 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. -

Sep 08, 2017
Athena Diagnostics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 30, 2022
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: R305W has decreased membrane expression and basal activity (Lubrano-Berthelier et al., 2006; Roubert et al., 2010); Identified in the heterozygous state in patients with obesity in published literature (Abawi et al., 2022; Kleinendorst et al., 2018; Lubrano-Berthelier et al., 2006; Polk et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12851297, 18559663, 20696697, 16507637, 29970488, 35898454, 29031731, 32952152, 28284973, 31417496, 26119161, 26244670) -

Sep 04, 2019
Genetic Services Laboratory, University of Chicago
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

DNA sequence and deletion/duplication analysis of the MC4R gene demonstrated a sequence change, c.913C>T, in exon 1 that results in an amino acid change, p.Arg305Trp. The p.Arg305Trp change has been identified in three individuals with obesity (PMIDs: 29970488, 20696697, 16507637). The p.Arg305Trp change was found to be a de novo change in one of these individuals (PMID 29970488). This sequence change has been described in the gnomAD database with a frequency of 0.011% in Latino populations (dbSNP rs549442687). The p.Arg305Trp change affects a highly conserved amino acid residue located in a domain of the MC4R protein that is known to be functional. The p.Arg305Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated that this sequence change results in both reduced basal activity and _-MSH potency (PMID: 20696697, 16507637). -

Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
Feb 25, 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
Aug 22, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

The MC4R c.913C>T variant is predicted to result in the amino acid substitution p.Arg305Trp. This variant has been reported in the heterozygous state in a number of patients with obesity, including one with a de novo variant (Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Stutzmann et al. 2008. PubMed ID: 18559663; Kleinendorst et al. 2018. PubMed ID: 29970488). Functional studies have shown that the c.913C>T variant leads to a reduction in protein function (Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Stutzmann et al. 2008. PuMed ID: 18559663; Roubert et al. 2010. PubMed ID: 20696697). A different substitution at the same amino acid (p.Arg305Gln) has also been reported to cause obesity (see for example Reinehr et al. 2009. PubMed ID: 18997677). Taken together, we consider the evidence sufficient to classify the c.913C>T (p.Arg305Trp) variant found in this patient as likely pathogenic. -

Obesity Uncertain:1
Jan 22, 2020
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

The p.Arg305Trp variant in MC4R has been reported in 2 individuals (including 1 Jamaican individual) with Obesity (PMID: 16507637, 20696697; Alsters 2016), and has been identified in 0.01129% (4/35436) of Latino chromosomes and 0.006533% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549442687). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. 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 in ClinVar (Variation ID: 586138). In vitro functional studies provide some evidence that the p.Arg305Trp variant may impact protein function (PMID: 16507637, 20696697). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PS4_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Uncertain
0.39
Sift
Uncertain
0.0020
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.88
P
Vest4
0.97
MVP
0.83
MPC
0.10
ClinPred
0.65
D
GERP RS
6.1
Varity_R
0.71
gMVP
0.98
Mutation Taster
=20/80
disease causing (ClinVar)

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.

Other links and lift over

dbSNP: rs549442687; hg19: chr18-58038670; COSMIC: COSV55352780; API