rs13447324

Positions:

chr18-60372245-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16U:1

Conservation

PhyloP100: 1.49

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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 32 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].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.105C>A	p.Tyr35Ter	stop_gained	1/1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
MC4R	ENST00000299766.5 linkuse as main transcript	c.105C>A	p.Tyr35Ter	stop_gained	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42900G>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42900G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

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:

AN:

251374

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135858

show subpopulations

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:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727248

show subpopulations

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:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

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.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2018	- -
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	GeneDx	Sep 25, 2024	Reported multiple times in association with obesity (PMID: 10199800, 12970296, 15486053, 16507637, 18559663); Published functional studies demonstrate that Y35X leads to impaired cAMP responses and absent binding of NDP-alphaMSH (PMID: 12970296, 15486053); Nonsense variant predicted to result in protein truncation, as the last 298 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 19091795, 16752916, 18559663, 16507637, 15486053, 29273807, 29970488, 31447099, 10577903, 19301229, 20966905, 12646665, 18801902, 16616374, 16274851, 36325899, 34083135, 10199800, 12970296, 37601970) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, 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	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 18, 2022	- -

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	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). -
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	- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:3

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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Sep 18, 2024	ACMG Criteria: PVS1, PM2_P, PS3, PP5; Variant was found in a heterozygous state -

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

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.84

MutationTaster

Benign

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over