rs747681609

chr18-60371856-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_005912.3(MC4R):c.494G>A(p.Arg165Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 19) in uniprot entity MC4R_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_005912.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-60371857-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1284736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 18-60371856-C-T is Pathogenic according to our data. Variant chr18-60371856-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 327713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.494G>A	p.Arg165Gln	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.494G>A	p.Arg165Gln	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42511C>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42511C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251310 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.0000335 AC: 49 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The MC4R c.494G>A (p.Arg165Gln) variant has been reported in at least four studies in a heterozygous state in a total of 18 individuals with severe early-onset obesity, severe obesity, or juvenile onset obesity (Farooqi et al. 2000; Farooqi et al. 2003; Ma et al. 2004; Larsen et al. 2005). In one family, the p.Arg165Gln variant was detected in both the affected father and affected son. The p.Arg165Gln variant was absent from 2,070 control alleles but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies demonstrated that the p.Arg165Gln variant was expressed but defective in trafficking to the cell surface and was retained intracellularly. The variant was also shown to have impaired ligand-stimulated ERK 1/2 activation, a partial cAMP response when stimulated with alpha-MSH, and to exhibit a 17-fold decrease in affinity to NDP-MSH as a result of a markedly reduced ligand binding capacity (Nijenhuis et al. 2003; Yeo et al. 2003; He et al. 2014). The Arg165 residue is conserved across thirty species (Staubert et al. 2007). Based on the evidence, the p.Arg165Gln variant is classified as pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg165Gln variant in MC4R has been reported in 20 individuals with Obesity, segregated with disease in 2 affected relatives from one family, (PMID: 10903343, 12646665, 15448103, 15486053, 29861388), and has been identified in 0.005441% (1/18380) of East Asian chromosomes and 0.004399% (5/113650) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747681609). 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 likely pathogenic in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact expression, ligand binding, and protein activity (PMID: 12588803, 12690102, 12646665, 15486053, 20826565). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg165Gly, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 22106157, 24276017, 25332687). 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, PM2_Supporting, PM5_supporting (Richards 2015). -

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

Sep 26, 2018

The p.Arg165Gln variant in MC4R has been reported in >15 individuals with severe obesity and segregated with disease in one affected relative (Farooqi 2003, Ma 2004, Larsen 2005). This variant has been identified in 6/111582 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is reported in ClinVar (Variation ID: 327713). In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact protein function (Nijenhuis 2003, Farooqi 2003, Larsen 2005, Xiang 2006, Thearle 2012); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg165Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg165Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP3, PS3_Supporting, PM2_Supporting. -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Nov 30, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 05, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 165 of the MC4R protein (p.Arg165Gln). This variant is present in population databases (rs747681609, gnomAD 0.006%). This missense change has been observed in individual(s) with MC4R-related obesity (PMID: 10903343, 12646665, 15486053, 18835933, 33889637). ClinVar contains an entry for this variant (Variation ID: 327713). 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 have shown that this missense change affects MC4R function (PMID: 12588803, 12690102, 15486053, 16752916, 24276017, 31002796). This variant disrupts the p.Arg165 amino acid residue in MC4R. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10903341, 12690102, 16752916). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.95		Loss of MoRF binding (P = 0.0916);
MVP		0.86
MPC		0.046
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.92

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

Other links and lift over

dbSNP: rs747681609; hg19: chr18-58039089; COSMIC: COSV55351652;