rs766665118

chr18-60371901-G-Achr18-60371901-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM1PP3_StrongPP5_Very_StrongBS2

The NM_005912.3(MC4R):c.449C>T(p.Thr150Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

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 10 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 19) in uniprot entity MC4R_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_005912.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 18-60371901-G-A is Pathogenic according to our data. Variant chr18-60371901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
MC4R	ENST00000299766.5 linkuse as main transcript	c.449C>T	p.Thr150Ile	missense_variant	1/1	NM_005912.3	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42556G>A		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42556G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251398

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000425

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Obesity

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	The c.449C>T;p.(Thr150Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 435829; PMID: 26588347; 24611737; 19244934; 18559663; 17590021; 17492953; 16507637) - PS4. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29311635) - PS3_supporting. The variant is present at low allele frequencies population databases (rs766665118 – gnomAD 0.00002628%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 24611737; 19244934) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in multiple unrelated individuals with obesity and segregated with disease in two individuals from the same family (PMID: 10903341, 16507637, 17492953, 19244934, 24611737, 26588347). Functional studies demonstrate that it significantly reduces protein activity, ligand binding, and response to ligand (PMID: 10903341, 16083993, 16507637, 16752916). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0072% (18/251398) and thus is presumed to be rare. The c.449C>T (p.Thr150Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.449C>T (p.Thr150Ile) variant is classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 13, 2014	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Thr150Ile variant in MC4R has been reported in at least 6 individuals with Obesity or who are overweight, segregated with disease in 2 obese relatives from 1 family (PMID: 16507637, 10903341, 17492953, 19244934, 26588347, 24611737), and has been identified in 0.04626% (16/34586) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766665118). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 likely pathogenic and pathogenic in ClinVar (Variation ID: 435829). In vitro functional studies provide some evidence that the p.Thr150Ile variant may impact protein activity, ligand binding, and response to the ligand (PMID: 10903341, 16083993, 16752916, 16507637). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in an important, well-established functional domain near the DRY motif. Variants in this position near the DRY motif are expected to impact receptor function in multiple receptor types (PMID: 16083993). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderate, PS4_Moderate, PM1 (Richards 2015). -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 21, 2022

- -

Obesity, autosomal dominant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 18, 2016

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MC4R function (PMID: 10903341, 16752916, 17590021). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 435829). This missense change has been observed in individual(s) with obesity (PMID: 10903341, 16507637, 18559663, 24611737, 26588347). This variant is present in population databases (rs766665118, gnomAD 0.05%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 150 of the MC4R protein (p.Thr150Ile). -

MC4R-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

The MC4R c.449C>T variant is predicted to result in the amino acid substitution p.Thr150Ile. This variant has been reported to be causative for autosomal dominant obesity (Albuquerque et al. 2014. PubMed ID: 24611737; Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Serra-Juhe et al. 2019. PubMed ID: 30926952). In vitro functional analyses indicate that the p.Thr150Ile variant results in partial loss of activity (Stutzmann et al. 2008. PubMed ID: 18559663; Vaisse et al. 2000. PubMed ID: 10903341; Lotta et al. 2019. PubMed ID: 31002796). This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.071

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.93

Loss of catalytic residue at T150 (P = 0.0469);

MVP

0.85

MPC

0.10

ClinPred

0.96

GERP RS

5.7

Varity_R

0.95

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

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