18-60371443-C-G

Position:

• chr18-60371443-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005912.3(MC4R):​c.907G>C​(p.Ala303Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005912.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.907G>C	p.Ala303Pro	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.907G>C	p.Ala303Pro	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42098C>G		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42098C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MC4R-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The MC4R c.907G>C variant is predicted to result in the amino acid substitution p.Ala303Pro. This variant has been reported heterozygous in four individuals with high body mass index of Pima Indian heritage living in Arizona (Thearle et al. 2012. PubMed ID: 22106157; Hohenadel et al. 2013. PubMed ID: 24276017). This variant is not present in a large population database, indicating it is rare. Functional studies have shown that this variant reduces MC4R activity and maximum response (Table 3, Thearle et al. 2012. PubMed ID: 22106157; Hohenadel et al. 2013. PubMed ID: 24276017). Of note, another variant impacting this same amino acid, c.907G>A (p.Ala303Thr), has been reported as pathogenic in multiple individuals with obesity (Ahituv et al. 2007. PubMed ID: 17357083; Calton et al. 2009. PubMed ID: 19091795; Tan et al. 2009. PubMed ID: 18801902). This variant is interpreted as pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2023

Identified in individuals with increased body mass index from a large cohort of participants in a longitudinal health study, although additional clinical information was not provided (Thearle et al., 2012; Hohenadel et al., 2014); Published functional studies suggest a damaging effect with loss of function, although one study suggests this variant retains partial activity (He et al., 214; Hohenadel et al., 2014; Thearle et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32640185, 22106157, 24276017, 25332687) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.82		Loss of methylation at R305 (P = 0.115);
MVP		0.82
MPC		0.11
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.99

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

Other links and lift over

dbSNP: rs762251697; hg19: chr18-58038676;