rs13447324

chr18-60372245-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_005912.3(MC4R):c.105C>A(p.Tyr35Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,092 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: MC4R NM_005912.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 1.49

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 77 pathogenic variants in the truncated region.
• PP5: Variant 18-60372245-G-T is Pathogenic according to our data. Variant chr18-60372245-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60372245-G-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.105C>A	p.Tyr35Ter	stop_gained	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.105C>A	p.Tyr35Ter	stop_gained	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42900G>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42900G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152202 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: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251374 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135858

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000616 AC: 90 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74354

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: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2023	Reported multiple times in association with obesity (Hinney et al., 1999; Hinney et al., 2003; Larsen et al., 2005; Lubrano-Berthelier et al., 2006; Stutzmann et al., 2008); Published functional studies demonstrate that Y35X leads to impaired cAMP responses and absent binding of NDP-alphaMSH (Hinney et al., 2003; Larsen et al., 2005); Nonsense variant predicted to result in protein truncation, as the last 298 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 19091795, 16752916, 12970296, 18559663, 16507637, 15486053, 29273807, 29970488, 10199800, 31447099, 10577903, 19301229, 20966905, 12646665, 18801902, 16616374, 16274851) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2023	This sequence change creates a premature translational stop signal (p.Tyr35*) in the MC4R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 298 amino acid(s) of the MC4R protein. This variant is present in population databases (rs13447324, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features consistent with MC4R-related obesity (PMID: 10199800, 12970296, 15486053, 29970488). ClinVar contains an entry for this variant (Variation ID: 14318). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MC4R function (PMID: 12970296, 16507637, 16752916). This variant disrupts a region of the MC4R protein in which other variant(s) (p.Ile301Thr) have been determined to be pathogenic (PMID: 10903341, 12690102, 16507637, 16752916, 18559663). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Obesity Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 06, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The MC4R c.105C>A (p.Tyr35Ter) stop-gained variant has been identified in a heterozygous state in at least 38 individuals with obesity. In almost all of these reports, the variant was found in cis with another variant, p.Asp37Val (Hinney et al. 1999; Hinney et al. 2003; Farooqi et al. 2003; Stutzmann et al. 2008; Tan et al. 2009; Calton et al. 2009; Larsen et al. 2009; van den Berg et al. 2011). The p.Tyr35Ter variant was absent from over 4,000 controls and is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Lubrano-Berthelier et al. (2006) demonstrated a complete lack of membrane expression of the p.Tyr35Ter variant protein as well as a significantly impaired basal receptor activity and reduced response to a receptor agonist, both to less than 10% of wildtype. It has been shown that the C-terminal tail of the receptor contains a signal for cell surface expression, hence any truncation of the protein upstream of this signal as is predicted for the p.Tyr35Ter variant would result in intracellular retention of the variant receptor (MacKenzie, 2006). Based on the collective evidence and the potential impact of stop-gained variants, the p.Tyr35Ter variant is classified as pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Tyr35Ter variant in MC4R has been reported in at least 46 individuals (including 9 Danish, 5 German, 3 Dutch, and 1 Norweigan individuals) with Obesity (PMID: 10199800, 19301229, 15486053, 12970296, 16507637, 20966905, 10577903, 18801902, 18559663, 19091795), and has been identified in 0.01549% (20/129114) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447324). This variant was also reported in a non-obese and non-overweight individual (PMID: 10577903). 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 pathogenic in ClinVar, and is often reported in cis with the p.Asp37Val variant (Variation ID: 14318). In vitro functional studies provide some evidence that the p.Tyr35Ter variant may eliminate receptor activity and cell membrane expression (PMID: 16507637, 20966905). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 35. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without regions important to function. Heterozygous loss of function of the MC4R gene is an established disease mechanism in Obesity. In summary, this variant meets criteria to be classified as pathogenic for Obesity in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Obesity. ACMG/AMP Criteria applied: PVS1_Strong, PS4, PS3, PM2_Supporting (Richards 2015). -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 29, 2021	- -

Obesity due to melanocortin 4 receptor deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 19, 2018

The p.Tyr35X variant in MC4R has been reported in >15 individuals with obesity and segregated with disease in at least 8 relatives (Hinney 1999, Sina 1999, Hinney 2003, Larsen 2005, Lubrano-Berthelier 2006, Stutzmann 2008, Wangensteen 2009, Calton 2009, van den Berg 2011). The Tyr35X variant has been identified in 20/126634 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447324). This variant leads to a premature termination codon at position 35, which is predicted to lead to a truncated or absent protein. Please note, this variant is commonly seen in cis (on same allele) with p.Asp37Val, which would not be translated since it is downstream of the premature stop codon. In vitro expression of the p.Tyr35X-MC4R protein demonstrated absent cell surface expression, ligand binding, and cAMP response (Larsen 2005, Xiang 2006, Lubrano-Berthelier 2006, Brumm 2012). Haploinsufficiency of the MC4R gene is an established disease mechanism in MC4R-related obesity. In summary, this variant meets criteria to be classified as pathogenic for MC4R-related obesity in an autosomal dominant. ACMG/AMP Criteria applied: PVS1_Strong, PS4, PS3, PP1_Strong. -

Schizophrenia Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

UCL Genetics Institute, UCL

Dec 23, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.60
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs13447324; hg19: chr18-58039478;