rs2229616

Positions:

chr18-60372043-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_005912.3(MC4R):c.307G>A(p.Val103Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0182 in 1,614,174 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 14 hom., cov: 32)

Exomes 𝑓: 0.018 ( 267 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:10

Conservation

PhyloP100: 6.14

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 Benign. Variant got -18 ACMG points.

PM1

In a helix (size 28) in uniprot entity MC4R_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005912.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0067133605).

BP6

Variant 18-60372043-C-T is Benign according to our data. Variant chr18-60372043-C-T is described in ClinVar as [Benign]. Clinvar id is 218330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60372043-C-T is described in Lovd as [Benign]. Variant chr18-60372043-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2350/152308) while in subpopulation SAS AF= 0.0243 (117/4816). AF 95% confidence interval is 0.0207. There are 14 homozygotes in gnomad4. There are 1116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2350 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.307G>A	p.Val103Ile	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.307G>A	p.Val103Ile	missense_variant	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42698C>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42698C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2350

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0200

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0161

AC:

4057

AN:

251448

Hom.:

AF XY:

0.0167

AC XY:

2276

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.0216

Gnomad SAS exome

AF:

0.0224

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0185

AC:

26996

AN:

1461866

Hom.:

267

Cov.:

AF XY:

0.0186

AC XY:

13508

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.00459

Gnomad4 EAS exome

AF:

0.0157

Gnomad4 SAS exome

AF:

0.0212

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.0198

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0154

AC:

2350

AN:

152308

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1116

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0157

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0199

Gnomad4 SAS

AF:

0.0243

Gnomad4 FIN

AF:

0.0120

Gnomad4 NFE

AF:

0.0182

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0174

AC:

2116

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0164

EpiControl

AF:

0.0177

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Obesity

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Sep 18, 2014	- -
protective, no assertion criteria provided	case-control	UCL Genetics Institute, UCL	Dec 23, 2014	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Imperial College London Diabetes Centre, Mubadala Healthcare

May 01, 2020

- -

MELANOCORTIN 4 RECEPTOR POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 18, 2019

ACMG criteria: BP4 (REVEL 0.050 + 6 predictors; not using PP3/4 predictors), BA1 (overall MAF in gnomAD 1.6%; over 2% in multiple subpop), BS2 (51 homozygotes in gnomAD, 237 cases and 277 controls in type2diabetesgenetics.org)=benign -

OBESITY, RESISTANCE TO

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

MC4R-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2021

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

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.070

REVEL

Benign

0.050

Sift

Benign

0.25

Sift4G

Benign

0.63

Polyphen

0.025

Vest4

0.061

MPC

0.022

ClinPred

0.017

GERP RS

5.9

Varity_R

0.22

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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