rs549442687

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP3PP5BS2

The NM_005912.3(MC4R):c.913C>T(p.Arg305Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,068 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R305Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.54

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005912.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-60371436-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

PP5

Variant 18-60371437-G-A is Pathogenic according to our data. Variant chr18-60371437-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586138.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.913C>T	p.Arg305Trp	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
MC4R	ENST00000299766.5 linkuse as main transcript	c.913C>T	p.Arg305Trp	missense_variant	1/1	NM_005912.3	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42092G>A		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42092G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251396

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 04, 2019	DNA sequence and deletion/duplication analysis of the MC4R gene demonstrated a sequence change, c.913C>T, in exon 1 that results in an amino acid change, p.Arg305Trp. The p.Arg305Trp change has been identified in three individuals with obesity (PMIDs: 29970488, 20696697, 16507637). The p.Arg305Trp change was found to be a de novo change in one of these individuals (PMID 29970488). This sequence change has been described in the gnomAD database with a frequency of 0.011% in Latino populations (dbSNP rs549442687). The p.Arg305Trp change affects a highly conserved amino acid residue located in a domain of the MC4R protein that is known to be functional. The p.Arg305Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated that this sequence change results in both reduced basal activity and _-MSH potency (PMID: 20696697, 16507637). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Published functional studies demonstrate a damaging effect: R305W has decreased membrane expression and basal activity (Lubrano-Berthelier et al., 2006; Roubert et al., 2010); Identified in the heterozygous state in patients with obesity in published literature (Abawi et al., 2022; Kleinendorst et al., 2018; Lubrano-Berthelier et al., 2006; Polk et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12851297, 18559663, 20696697, 16507637, 29970488, 35898454, 29031731, 32952152, 28284973, 31417496, 26119161, 26244670) -

Obesity due to melanocortin 4 receptor deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 25, 2022

proposed classification - variant undergoing re-assessment, contact laboratory -

Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg305Trp variant in MC4R has been reported in 2 individuals (including 1 Jamaican individual) with Obesity (PMID: 16507637, 20696697; Alsters 2016), and has been identified in 0.01129% (4/35436) of Latino chromosomes and 0.006533% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549442687). 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 in ClinVar (Variation ID: 586138). In vitro functional studies provide some evidence that the p.Arg305Trp variant may impact protein function (PMID: 16507637, 20696697). 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. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PS4_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

0.090

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.88

Vest4

0.97

MVP

0.83

MPC

0.10

ClinPred

0.65

GERP RS

6.1

Varity_R

0.71

gMVP

0.98

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