dbSNP rs747681609: MC4R:p.Arg165Gln (chr18-60371856-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 21P and 4B. PS3PM1PM5PP2PP3_StrongPP5_Very_StrongBS2

The NM_005912.3(MC4R):c.494G>A(p.Arg165Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000409977: In vitro functional studies demonstrated that the p.Arg165Gln variant was expressed but defective in trafficking to the cell surface and was retained intracellularly. The variant was also shown to have impaired ligand-stimulated ERK 1/2 activation, a partial cAMP response when stimulated with alpha-MSH, and to exhibit a 17-fold decrease in affinity to NDP-MSH as a result of a markedly reduced ligand binding capacity (Nijenhuis et al. 2003" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.91

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

inherited obesity
Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
obesity due to melanocortin 4 receptor deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000409977: In vitro functional studies demonstrated that the p.Arg165Gln variant was expressed but defective in trafficking to the cell surface and was retained intracellularly. The variant was also shown to have impaired ligand-stimulated ERK 1/2 activation, a partial cAMP response when stimulated with alpha-MSH, and to exhibit a 17-fold decrease in affinity to NDP-MSH as a result of a markedly reduced ligand binding capacity (Nijenhuis et al. 2003; Yeo et al. 2003; He et al. 2014).; SCV001423086: "In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact expression, ligand binding, and protein activity (PMID: 12588803, 12690102, 12646665, 15486053, 20826565)."; SCV004297609: Experimental studies have shown that this missense change affects MC4R function (PMID: 12588803, 12690102, 15486053, 16752916, 24276017, 31002796).; SCV006308160: Published functional studies demonstrate a damaging effect with lack of binding to NDP-alphaMSH (PMID: 15486053);; SCV004848248: "In vitro functional studies provide some evidence that the p.Arg165Gln variant may impact protein function" (Nijenhuis 2003, Farooqi 2003, Larsen 2005, Xiang 2006, Thearle 2012); SCV005351223: In vitro analysis of the p.Arg165Gln change demonstrated impaired function of the p.Arg165Gln variant protein, including high levels of intracellular retention compared to wild type and reduced binding to NDP-αMSH (Farooqi et al. 2003. PubMed ID: 12646665; Larsen et al. 2005. PubMed ID: 15486053; René et al. 2010. PubMed ID: 20826565).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005912.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-60371857-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1284736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.0099 (below the threshold of 3.09). Trascript score misZ: 0.30396 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited obesity, obesity due to melanocortin 4 receptor deficiency.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 18-60371856-C-T is Pathogenic according to our data. Variant chr18-60371856-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 327713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 49 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.494G>A	p.Arg165Gln	missense	Exon 1 of 1	NP_005903.2	P32245

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MC4R	ENST00000299766.5	TSL:6 MANE Select	c.494G>A	p.Arg165Gln	missense	Exon 1 of 1	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1		n.113+42511C>T		intron	N/A
ENSG00000285681	ENST00000658928.1		n.156+42511C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251310

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000610

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (2)

Obesity (2)

Early onset severe obesity (1)

MC4R-related disorder (1)

Obesity due to melanocortin 4 receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.084

MutationAssessor

Pathogenic

3.7

PhyloP100

7.9

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.96

MutPred

0.95

Loss of MoRF binding (P = 0.0916)

MVP

0.86

MPC

0.046

ClinPred

0.99

GERP RS

5.8

Varity_R

0.90

gMVP

0.92

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over