Variant rs369841551 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005912.3(MC4R):c.466C>T(p.Gln156*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,036 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MC4R
NM_005912.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 8.06

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 20 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-60371884-G-A is Pathogenic according to our data. Variant chr18-60371884-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60371884-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC4R	NM_005912.3 link	c.466C>T	p.Gln156*	stop_gained	Exon 1 of 1	ENST00000299766.5	NP_005903.2	P32245

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MC4R	ENST00000299766.5 link	c.466C>T	p.Gln156*	stop_gained	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1 link	n.113+42539G>A		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1 link	n.156+42539G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 19, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln156*) in the MC4R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the MC4R protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with obesity (PMID: 30586318). ClinVar contains an entry for this variant (Variation ID: 562356). This variant disrupts a region of the MC4R protein in which other variant(s) (p.Ile301Thr) have been determined to be pathogenic (PMID: 10903341, 12690102, 16507637, 16752916, 18559663). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in individuals with obesity in the published literature, however segregation studies were not completed (Vollbach et al., 2017; Namjou et al., 2021); Identified in an individual with kidney disease in the published literature, and information on body mass index was not provided (Groopman et al., 2019); Nonsense variant predicted to result in protein truncation, as the last 177 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31447099, 27654141, 29568105, 32952152, 30586318) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:2

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes

Pathogenic:1

Jun 15, 2017

Translational Genomics Laboratory, University of Maryland School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.466C>T variant in codon 156 (exon 1) of the melanocortin 4 receptor gene, MC4R, results in the generation of a stop codon and the expected loss of four of the seven transmembrane domains of the protein (10592235). The c.466C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Nonsense mutations in MC4R have been reported previously as autosomal dominant, monogenic causes of obesity (10199800, 12646665). All individuals found to have pathogenic mutations in MC4R in one study had severe hyperinsulinemia, even compared to obese controls (12646665). The c.466C>T variant was previously identified in a 12-year old boy with severe early-onset obesity (27654141). Additionally, multiple lines of computational evidence (SIFT, LRT, MutationTaster, CADD, GERP) predict this variant is probably damaging to the protein structure or function. ACMG criteria = PVS1, PM2, PP3 -

Obesity

Pathogenic:1

Jan 18, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.466C>T (p.Gln156*) variant has not been observed in the ExAC database, nor has been observed in our patient cohort but has been reported in dbSNP (rs369841551) with a minor allele frequency of 0.00008. This c.466C>T encodes for a nonsense codon in exon 1 at amino acid position 156 of the MC4R protein. This premature stop codon is predicted to result in a loss of function of the protein. It is thus classify as a pathogenic variant. -

MC4R-related disorder

Pathogenic:1

Feb 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC4R c.466C>T variant is predicted to result in premature protein termination (p.Gln156*). This variant has been reported in an individual with obesity (Table 1, Vollbach et al. 2017. PubMed ID: 27654141; Kohlsdorf et al. 2018. PubMed ID: 29568105). Furthermore, truncating variants upstream and downstream of this variant have been reported in individuals with autosomal dominant obesity phenotypes (Farooqi et al. 2003. PubMed ID: 12646665; Wang et al. 2006. PubMed ID: 17185898). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense 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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

Vest4

0.84

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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