18-60371448-A-G

Position:

• chr18-60371448-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005912.3(MC4R):​c.902T>C​(p.Ile301Thr) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 16 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, 13 uncertain in NM_005912.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 18-60371448-A-G is Pathogenic according to our data. Variant chr18-60371448-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 945179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.902T>C	p.Ile301Thr	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.902T>C	p.Ile301Thr	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42103A>G		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42103A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MC4R function (PMID: 10903341, 12690102, 16507637, 16752916). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 945179). This missense change has been observed in individual(s) with MC4R-related disease (PMID: 10903341, 18559663). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 301 of the MC4R protein (p.Ile301Thr). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	Published functional studies demonstrate a damaging effect (Lotta et al., 2019; Vaisse et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17590021, 16752916, 10903341, 18559663, 12690102, 16507637, 17628007, 18231126, 30811542, 29216354, 31002796) -

MC4R-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

The MC4R c.902T>C variant is predicted to result in the amino acid substitution p.Ile301Thr. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states in individuals with obesity, with compound heterozygotes and homozygotes noted to be more severely affected (Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Stutzmann et al. 2008. PubMed ID: 18559663). It segregated with disease in multiple families (Vaisse et al. 2000. PubMed ID: 1090334; Stutzmann et al. 2008. PubMed ID: 18559663). In vitro experimental studies suggest this variant affects protein function (see, for example, Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Nijenhuis et al. 2003. PubMed ID: 12690102). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Loss of stability (P = 0.0103);
MVP		0.84
MPC		0.11
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.88
gMVP		0.96

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: rs1915335064; hg19: chr18-58038681;