18-60372202-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_005912.3(MC4R):c.148G>A(p.Val50Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V50G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.02

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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

PM2

Very rare variant in population databases, with high coverage;

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 obesity due to melanocortin 4 receptor deficiency, inherited obesity.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.148G>A	p.Val50Met	missense	Exon 1 of 1	NP_005903.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MC4R	ENST00000299766.5	TSL:6 MANE Select	c.148G>A	p.Val50Met	missense	Exon 1 of 1	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1		n.113+42857C>T		intron	N/A
ENSG00000285681	ENST00000658928.1		n.156+42857C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:1

Aug 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:1

Apr 01, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17628007, 12959994, 20462274, 31002796, 12499395, 22817722, 32949766, 31855179, 11487744, 28433713, 20696697, 26229975, 29031731, 25332687, 19184404)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.86

MutPred

0.85

Loss of catalytic residue at V50 (P = 0.1026)

MVP

0.70

MPC

0.10

ClinPred

0.97

GERP RS

5.6

Varity_R

0.31

gMVP

0.79

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over