rs52820871

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005912.3(MC4R):c.751A>C(p.Ile251Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0107 in 1,614,030 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 117 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 6.70

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:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01031518).

BP6

Variant 18-60371599-T-G is Benign according to our data. Variant chr18-60371599-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 218329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60371599-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0074 (1126/152238) while in subpopulation NFE AF= 0.0114 (773/68004). AF 95% confidence interval is 0.0107. There are 6 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC4R	NM_005912.3 link	c.751A>C	p.Ile251Leu	missense_variant	Exon 1 of 1	ENST00000299766.5	NP_005903.2	P32245

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MC4R	ENST00000299766.5 link	c.751A>C	p.Ile251Leu	missense_variant	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1 link	n.113+42254T>G		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1 link	n.156+42254T>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00740

AC:

1126

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00692

AC:

1740

AN:

251350

Hom.:

AF XY:

0.00704

AC XY:

957

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.0111

AC:

16168

AN:

1461792

Hom.:

117

Cov.:

AF XY:

0.0107

AC XY:

7775

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.00979

GnomAD4 genome

AF:

0.00740

AC:

1126

AN:

152238

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.0113

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00628

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0116

AC:

100

ExAC

AF:

0.00684

AC:

830

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC4R: BS1, BS2 -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Obesity

Uncertain:1Benign:2

Dec 23, 2014

UCL Genetics Institute, UCL

Significance: protective

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jun 22, 2012

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

May 12, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Benign:1

Aug 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes

Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BP4 (REVEL 0.138 + 7 predictors), BA1 (1.1% in gnomAD ENF), BS2 (142 cases and 120 controls in type2diabetesgenetics.org); susceptibility factor with conflicting data (protective and obesity susceptibility), called polymorphism in multiple publications=benign -

MC4R-related disorder

Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.17

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.0

PrimateAI

Uncertain

0.74

PROVEAN

Benign

1.8

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.23

MVP

0.53

MPC

0.014

ClinPred

0.016

GERP RS

5.8

Varity_R

0.14

gMVP

0.90

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