rs772393451

Positions:

chr18-60371601-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PP3_StrongPP5_Very_StrongBS2

The NM_005912.3(MC4R):c.749T>A(p.Leu250Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,122 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 18-60371601-A-T is Pathogenic according to our data. Variant chr18-60371601-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.749T>A	p.Leu250Gln	missense_variant	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.749T>A	p.Leu250Gln	missense_variant	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42256A>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42256A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251338

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Obesity

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Leu250Gln variant in MC4R has been reported in 3 individuals (including 1 European individual) with Obesity (PMID: 10903341, 16507637, 18559663), and has been identified in 0.002891% (1/34586) of Latino chromosomes and 0.002640% (3/113656) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772393451). 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 as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 549551). In vitro functional studies provide some evidence that the p.Leu250Gln variant may impact cell membrane expression and constitutively activate the protein receptor (PMID: 16611215, 23791567, 12499395, 16507637, 12690102). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies also provide some evidence that multiple, unique missense variants at the same position impact the protein and that this position is important for protein function (PMID: 16611215). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PP3, PS4_Supporting, PM5_Supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 10, 2017	This c.749T>A (p.Leu250Gln) has previously been reported in multiple patients presenting with obesity [PMID 10903341, 16507637, 18559663, 12690102]. Functional assays showed that the receptor displayed high constitutive activity [PMID 12690102, 16611215, 16507637, 23791567]. However, cell surface expression level of the p.Leu250Gln mutant was decreased by about half of wild type [PMID 12690102, 16507637]. Thus the mechanism of pathogenicity of this variant in unclear at this time. This variant is conserved in mammals. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-58038834-A-T). While not validated for clinical use, the computer-based algorithms predict this p.Leu250Gln change to be deleterious. It is thus interpreted as a likely pathogenic variant. -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 19, 2021

- -

MC4R-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The MC4R c.749T>A variant is predicted to result in the amino acid substitution p.Leu250Gln. This variant has been reported in individuals with obesity (Vaisse et al. 2000. PubMed ID: 10903341; Nijenhuis et al. 2003. PubMed ID: 12690102; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637). Functional studies indicate this variant alters membrane expression and leads to high constitutive activity (Vaisse et al. 2000. PubMed ID: 10903341; Nijenhuis et al. 2003. PubMed ID: 12690102; Lubrano-Berthelier et al. 2006. PubMed ID: 16507637; Proneth et al. 2006. PubMed ID: 16611215; Xiang et al. 2006. PubMed ID: 16752916). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/549551/). Taken together, we interpret this variant as likely pathogenic. -

Monogenic diabetes

Uncertain:1

Uncertain significance, flagged submission

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 10, 2017

ACMG Criteria:PP3 (8 predictors), BP4 (3 predictors) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MVP

0.80

MPC

0.10

ClinPred

0.99

GERP RS

5.8

Varity_R

0.97

gMVP

0.99

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