Variant 18-60371513-GCA-GCACA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_005912.3(MC4R):c.836_837insTG(p.Phe280AlafsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

MC4R
NM_005912.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.

PP5

Variant 18-60371513-G-GCA is Pathogenic according to our data. Variant chr18-60371513-G-GCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.836_837insTG	p.Phe280AlafsTer12	frameshift_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.836_837insTG	p.Phe280AlafsTer12	frameshift_variant	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42175_156+42176dup		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42175_113+42176dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251368

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Obesity

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Phe280Alafs variant in MC4R has been reported in at least 4 individuals from the UK with obesity, segregated with disease in at these four affected relatives from two families (PMID: 18801902,12646665), and has been identified in 0.0009% (1/113664) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922687). This variant has also been reported in ClinVar as pathogenic (Variation ID: 36487). In vitro functional studies provide evidence that the p.Phe280Alafs variant may impact protein function (PMID: 12646665). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 280 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated protein since this is a single exon gene that is not predicted to undergo nonsense mediated decay. Heterozygous loss of function of the MC4R gene is an established disease mechanism in obesity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PVS1_strong, PM2_supporting, PP1, PS4_supporting (Richards 2015). -

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

Mar 01, 2022

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

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2024

Identified in unrelated individuals with obesity referred for genetic testing at GeneDx and in the published literature (PMID: 12646665); Frameshift variant predicted to result in protein truncation, as the last 53 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies show the variant results in loss of function (PMID: 12646665); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16752916, 24077912, 10903343, 12646665, 16274851, 18801902, 27701398) -

MC4R-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2024

The MC4R c.835_836dupTG variant is predicted to result in a frameshift and premature protein termination (p.Phe280Alafs*12). This variant has been reported to be causative for severe early onset obesity (reported as insertion of GT at codon 279 in Farooqi et al. 2000. PubMed ID: 10903343; Farooqi et al. 2003. PubMed ID: 12646665). An in vitro functional study showed no activity of the protein (Farooqi et al. 2003. PubMed ID: 12646665). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MC4R are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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