18-60372144-A-G

Variant names:

• chr18-60372144-A-G
• rs751160202
• NM_005912.3:c.206T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PM1 PM5 PP2 PP3_Strong BS2

The NM_005912.3(MC4R):​c.206T>C​(p.Ile69Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,888 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I69R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.32
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• inherited obesity

  Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
• obesity due to melanocortin 4 receptor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285681 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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, 7 uncertain in NM_005912.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-60372144-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 211442.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 obesity due to melanocortin 4 receptor deficiency, inherited obesity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• BS2: High AC in GnomAdExome4 at 45 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.206T>C	p.Ile69Thr	missense	Exon 1 of 1	NP_005903.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	ENST00000299766.5	TSL:6 MANE Select	c.206T>C	p.Ile69Thr	missense	Exon 1 of 1	ENSP00000299766.3
	ENSG00000285681	ENST00000650201.1		n.113+42799A>G		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+42799A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251350 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000639 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MC4R-related disorder Pathogenic:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC4R c.206T>C variant is predicted to result in the amino acid substitution p.Ile69Thr. This variant has been reported in the heterozygous and homozygous state in multiple individuals with early onset obesity (Tan et al. 2009. PubMed ID: 18801902; René et al. 2010. PubMed ID: 20826565; He et al. 2014. PubMed ID: 25332687; Saeed et al. 2020. PubMed ID: 32349990). Functional studies have shown that this variant causes significantly increased pERK1/2 levels, impaired cell surface trafficking, reduced level of binding ligand, and reduced ability to generate cAMP (Tan et al. 2009. PubMed ID: 18801902; René et al. 2010. PubMed ID: 20826565; Xiang et al. 2010. PubMed ID: 20462274; He et al. 2014. PubMed ID: 25332687). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.

not provided Uncertain:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 69 of the MC4R protein (p.Ile69Thr). This variant is present in population databases (rs751160202, gnomAD 0.006%). This missense change has been observed in individual(s) with obesity (PMID: 18801902, 32349990). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 18801902, 20462274, 20826565, 25332687). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.95		Loss of stability (P = 0.0254)
MVP		0.76
MPC		0.11
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.84
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs751160202; hg19: chr18-58039377;