Variant 18-60371598-ATC-A 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.750_751delGA(p.Ile251fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000328 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MC4R
NM_005912.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.70

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:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

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 12 pathogenic variants in the truncated region.

PP5

Variant 18-60371598-ATC-A is Pathogenic according to our data. Variant chr18-60371598-ATC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60371598-ATC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.750_751delGA	p.Ile251fs	frameshift_variant	1/1	ENST00000299766.5	NP_005903.2	P32245

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MC4R	ENST00000299766.5 linkuse as main transcript	c.750_751delGA	p.Ile251fs	frameshift_variant	1/1	6	NM_005912.3	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1 linkuse as main transcript	n.113+42254_113+42255delTC		intron_variant
ENSG00000285681	ENST00000658928.1 linkuse as main transcript	n.156+42254_156+42255delTC		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251364

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000794

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:

0.0000342

AC:

AN:

1461892

Hom.:

AF XY:

0.0000248

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000650

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:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this premature translational stop signal affects MC4R function (PMID: 12970296, 15126516, 20462274). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 435828). This premature translational stop signal has been observed in individual(s) with early-onset obesity (PMID: 12970296, 15126516, 20966905). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs13447339, gnomAD 0.08%). This sequence change creates a premature translational stop signal (p.Ile251Trpfs*34) in the MC4R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the MC4R protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2023	Published functional studies demonstrate loss of MC4R function (PMID: 12970296, 20462274); Frameshift variant predicted to result in abnormal protein length as the last 82 amino acids are replaced with 33 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 20462274, 15126516, 12970296, 34045736) -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -

Obesity, autosomal dominant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 29, 2016

- -

Obesity

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 22, 2020

The p.Ile251Trpfs variant in MC4R has been reported in six North African individuals with obesity, segregated with disease in these six affected relatives from one family (PMID: 15126516), and has been identified in 0.08% (8/10366) of Ashkenazi Jewish chromosomes, 0.004% (1/24968) of African chromosomes, and 0.0008% (1/129092) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs13447339). This variant has also been reported in ClinVar as pathogenic (Variation ID: 435828). In vitro functional studies provide some evidence that the p.Ile251Trpfs variant may impact protein function (PMID: 15126516). 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 251 and leads to a premature termination codon 34 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: PVS1_moderate, PP1_moderate, PS3_moderate (Richards 2015). -

MC4R-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The MC4R c.750_751delGA variant is predicted to result in a frameshift and premature protein termination (p.Ile251Trpfs*34). This variant has been reported in the heterozygous and homozygous states in individuals with obesity (see, for example, Lubrano-Berthelier et al. 2004. PubMed ID: 15126516; Welling et al. 2021. PubMed ID: 34291582; Zaitoon et al. 2023. PubMed ID: 37160786). In one family, the heterozygous parents and siblings were described as less severely affected than the homozygous proband (Lubrano-Berthelier et al. 2004. PubMed ID: 15126516). Functional characterization also revealed that this variant abolishes MC4R activity (Table 1, Hinney et al. 2003. PubMed ID: 12970296; Lubrano-Berthelier et al. 2004. PubMed ID: 15126516; Xiang et al. 2010. PubMed ID: 20462274). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in a large population database. 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

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